Alkynyl (hetero) aromatic ring compounds used for inhibiting protein kinase activity

ABSTRACT

Disclosed are alkynyl (hetero) aromatic ring compounds that inhibit protein tyrosine kinases, pharmaceutical compositions comprising same, preparations therefor and uses thereof. Specifically, disclosed are an alkynyl (hetero) aromatic ring compound represented by formula (I), and a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a crystal form, a prodrug or an isotope variant thereof. The disclosed compounds may be used in the treatment and/or prevention of diseases associated with protein tyrosine kinase, such as in preventing tumors.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a national application of PCT/CN2019/096062,filed on Jul. 16, 2019, which claims the priority of the Chinese PatentApplication No. 201810785390.6, filed on Jul. 17, 2018, and the ChinesePatent Application No. 201810798080.8, filed on Jul. 19, 2018. TheChinese Patent Application No. 201810785390.6 and No. 201810798080.8 areincorporated herein by reference as part of the disclosure of thepresent application.

TECHNICAL FIELD

The present disclosure belongs to the pharmaceutical technical field,and particularly relates to alkynyl (hetero)aromatic compounds havinginhibition effect on protein kinase activity, to pharmaceuticalcompositions containing the same, to preparation methods and usethereof.

BACKGROUND OF THE INVENTION

Protein tyrosine kinases (PTKs) are a kind of kinases that can catalyzethe transfer of γ-phosphate on ATP to protein tyrosine residues andactivate a protein enzyme system that functions as a functional proteinby catalyzing the phosphorylation of phenolic hydroxy groups on variousprotein tyrosine residues. Protein tyrosine kinase is very important inthe intracellular signaling pathway, which can regulate a series ofphysiological and biochemical processes such as cell growth,differentiation, and death. Abnormal expression of protein tyrosinekinase can lead to disorder of cell proliferation regulation, which inturn leads to the occurrence of tumors. In addition, the abnormalexpression of protein tyrosine kinases is also closely related to tumorinvasion and metastasis, tumor angiogenesis, and tumor resistance tochemotherapy. Protein kinases have become important targets of diseasetreatment. A non-limiting list of such kinases includes Ret(Reaarangedduring transfection), ABL1(E255K)-phosphorylated,ABL1(F317I)-nonphosphorylated, ABL1(F317I)-phosphorylated,ABL1(F317L)-nonphosphorylated, ABL1(F317L)-phosphorylated,ABL1(II396P)-nonphosphorylated, ABL1(II396P)-phosphorylated,ABL1(M351T)-phosphorylated, ABL1(Q252H)-nonphosphorylated,ABL1(Q252H)-phosphorylated, ABL1(T315I)-nonphosphorylated,ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated,ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ALK(L1196M),AMPK-alpha1, AMPK-alpha2, ANKK1, AURKB, AURKC, AXL, BLK, BMX, BRAF,BRAF(V600E), BRK, BTK, CAMK1, CAMKK1, CAMKK2, CDC2L1, CDC2L2, CDC2L5,CDK11, CDK2, CDK5, CDK7, CDK8, CDKL1, CDKL2, CDKL3, CHEK2, CIT, CLK1,CLK4, CSF1R, CSK, CTK, DDR1, DDR2, DLK, EGFR, EGFR(E746-A750del),EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del,P753S), EGFR(L747-T751del, Sins), EGFR(L858R), EGFR(L858R,T790M),EGFR(L861Q), EGFR(S752-1759del), EGFR(T790M), EPHA1, EPHA2, EPHA3,EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB4, EPHB6, ERBB2,ERBB4, ERK8, FAK, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3(G697C), FGFR4,FGR, FLT1, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD),FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q),FLT4, FRK, FYN, GAK, GCN2(Kin.Dom.2, S808G), HCK, HIPK4, HPK1,IKK-alpha, IKK-beta, IRAK1, IRAK4, ITK, JAK1(JH1domain-catalytic),JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic), JNK1, JNK2, JNK3,KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D),KIT(V559D,T670I), KIT(V559D,V654A), LCK, LIMK1, LIMK2, LOK, LRRK2,LRRK2(G2019S), LTK, LYN, MAK, MAP3K2, MAP3K3, MAP4K2, MAP4K3, MAP4K4,MAP4K5, MEK5, MELK, MERTK, MET, MET(M1250T), MINK, MKNK2, MLK1, MLK2,MLK3, MST1, MST1R, MST2, MUSK, MYLK2, MYO3A, MYO3B, NDR2, NEK1, NEK11,NEK4, NEK5, NEK9, NLK, p38-alpha, p38-beta, p38-delta, p38-gamma, PCTK2,PDGFRA, PDGFRB, PFCDPK1(P. falciparum), PFTAIRE2, PFTK1, PKAC-alpha,PKAC-beta, PYK2, RAF1, RET, RET(M918T), RET(V804L), RET(V804M), RIPK1,RIPK2, RIPK4, ROCK2, RPS6KA4(Kin.Dom. 1-N-terminal),RSK2(Kin.Dom.1-N-terminal), RSK3(Kin.DoN-terminal), S6K1, SIK, SLK, SRC,SRMS, SRPK1, STK33, STK35, STK36, SYK, TAK1, TAOK2, TAOK3, TEC, TESK1,TGFBR2, TIE1, TIE2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TTK,TXK, TYK2(JH1domain-catalytic), TYRO3, ULK3, VEGFR2, YES, YSK4, ZAK,ZAP70 or FGFR (Fibroblast growth factor receptor). Abnormal proteinkinase activity is associated with a variety of diseases, ranging fromnon-life-threatening diseases such as psoriasis to extremely seriousdiseases such as cancer.

Considering such a large number of protein kinases and numerous diseasesrelated to protein kinases, there is always a need in new types ofcompounds with increased selectivity. These compounds can be used asprotein kinase inhibitors and thus used in the treatment of proteintyrosine-related diseases.

The present disclosure relates to a new family of alkynyl heteroaromaticcompounds and their use in the treatment of cancer, bone diseases,metabolic diseases, inflammatory diseases and other diseases.

SUMMARY OF THE INVENTION

The present disclosure provides a new alkynyl (hetero)aromatic compoundand a composition containing the same and use thereof. The compound hasa wide range of biological and pharmacological activities, thereby theuse of these compounds in pharmaceutical composition and method fortreating protein kinase-mediated cancers, especially cancers mediated byAbl, Ret or Flt3 and their mutants are also related to.

In this regard, the present disclosure adopts the following technicalsolutions:

In the first aspect, the present disclosure provides a compound offormula (I):

wherein,

X₁, X₂ and X₃ are each independently selected from N or CR_(a);

Y is selected from N, O, S or CR_(a);

Z₁ and Z₂ are each independently selected from N or C, and Z₁ and Z₂ arenot N at the same time;

p, and q represent single bond or double bond, and there is one and onlyone double bond in p and q;

r, and s represent single bond or double bond, and there is one and onlyone double bond in r and s;

provided that when q and r are both single bond, Y is not CR_(a),

provided that when Z₁ is N, X₁, X₂, X₃ and Y are not CR_(a) at the sametime;

each R_(a) is independently selected from H, halogen, cyano, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₀R₁₁, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

-   -   ring A is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;    -   R₁ and R₃ are each independently absent or are H, halogen, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        —NR₁₂R₁₃, C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl,        wherein the said C₁₋₆ alkyl is optionally substituted with one,        two or three groups selected from C₁₋₃ alkyl, hydroxy or C₁₋₃        alkoxy;

R₂ is absent or is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl; wherein the said C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl and 4- to 7-membered heterocyclyl are each optionallysubstituted by one, two or three R₁₄;

wherein R₁ and R₂, or R₂ and R₃ can be combined to form a C₅₋₇cycloalkyl ring or 5- to 7-membered heterocyclyl ring, and wherein thesaid C₅₋₇ cycloalkyl ring and 5- to 7-membered heterocyclyl ring areeach independently substituted by one, two or three R₁₄;

R₄ is H, halogen, hydroxy, amino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

L is selected from —C(O)NR₉—, —NR₉C(O)—, —NR₉C(O)NR₉— or

ring B is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₅ is absent or is H, halogen, cyano, hydroxy, amino, C₁₋₆ alkyl or C₁₋₆alkoxy;

R₆ and R₇ are absent or are H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl, wherein the said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areoptionally substituted by one, two or three R₁₄;

R₈ is absent or is H or 5- to 7-membered heteroaryl, wherein the said 5-to 7-membered heteroaryl is optionally substituted by one, two or threeR₁₅;

wherein R₅ and R₆, R₆ and R₇, or R₇ and R₈ can be combined to form aC₅₋₇ cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ arylring or 5- to 12-membered heteroaryl ring, and wherein the said C₅₋₇cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ aryl ring and5- to 12-membered heteroaryl ring are each independently substituted byone, two or three R₁₄;

R₉, R₁₀ and R₁₁ are each independently selected from H or C₁₋₃ alkyl;

R₁₂ and R₁₃ are each independently H or C₁₋₆ alkyl; or Ru and R₁₃together with the nitrogen to which they attached form a 4- to7-membered heterocyclyl ring, wherein the formed 4- to 7-memberedheterocyclyl ring is optionally substituted by one, two or three R₁₅;

each R₁₄ is independently selected from halogen, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, —NR₁₆R₁₇, —C(O)NR₁₈R₁₉, C₃₋₇ cycloalkyl or 3- to7-membered heterocyclyl, wherein the said C₃₋₇ cycloalkyl and 3- to7-membered heterocyclyl are optionally substituted by one, two or threeR₁₅;

each R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl,C₁₋₃ alkoxy or —NR₂₀R₂₁;

R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ and R₂₁ are each independently H or C₁₋₃ alkyl;

or the pharmaceutically acceptable salts, stereoisomers, solvates,hydrates, crystal forms, prodrugs or isotopic variants thereof.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a compound of the present disclosure andpharmaceutically acceptable excipient(s). In a specific embodiment, thecompound of the present disclosure is provided in the pharmaceuticalcomposition in an effective amount. In a specific embodiment, thecompound of the present disclosure is provided in a therapeuticallyeffective amount. In a specific embodiment, the compound of the presentdisclosure is provided in a prophylactically effective amount.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a compound of the present disclosure andpharmaceutically acceptable excipient(s), which also contains othertherapeutic agent(s).

In another aspect, the present disclosure provides a kit comprising acompound of the present disclosure or the pharmaceutically acceptablesalts, stereoisomers, solvates, hydrates, crystal forms, prodrugs orisotopic variants thereof, optionally other therapeutic agent(s) andpharmaceutically acceptable carrier(s), adjuvant(s) or vehicle(s).

In another aspect, the present disclosure provides a method for treatinga protein kinase-related disease in a subject, the method includesadministering to the subject a compound of the present disclosure or thepharmaceutically acceptable salts, stereoisomers, solvates, hydrates,crystal forms, prodrugs or isotopic variants thereof, or thepharmaceutical composition. In a specific embodiment, the disease is atleast one selected from the following: pseudomyxoma, intrahepaticcholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, coloncancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oralcancer, lip cancer, acute myelogenous leukemia, acute lymphocyticleukemia, basal cell carcinoma, colon cancer, chronic myeloid leukemia,chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma,diffuse large B-cell lymphoma, carcinoma of the ampulla of Vater,bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer,nasal sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma,tongue cancer, astrocytoma, small cell lung cancer, infantile braintumor, infantile lymphoma, childhood leukaemia, small bowel cancer,meningeal cancer, esophageal cancer, glioma, neuroblastoma, kidneycancer, heart cancer, duodenal cancer, malignant soft tissue tumor,malignant bone cancer, malignant lymphoma, malignant mesothelioma,malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethralcancer, cancer of unknown primary, gastric lymphoma, gastric cancer,gastric carcinoid, gastrointestinal stromal tumor, Wilmes tumor, breastcancer, sarcoma, penile cancer, pharyngeal cancer, gestationaltrophoblastic disease, cervical cancer, endometrial cancer, uterinesarcoma, prostate cancer, metastatic bone cancer, metastatic braincancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginalcancer, spinal cancer, vestibular schwannoma, pancreatic cancer,salivary gland cancer, Kaposi sarcoma, Paget's disease, tonsilcarcinoma, squamous cell carcinoma, lung adenocarcinoma, lung squamouscell tumor, skin cancer, anal cancer, rhabdomyosarcoma, laryngealcancer, pleural cancer and thymic cancer. In a specific embodiment, theprotein kinase is selected from: Ret (Reaaranged during transfection),ABL1(E255K)-phosphorylated, ABL1(F317I)-nonphosphorylated,ABL1(F317I)-phosphorylated, ABL1 (F317L)-nonphosphorylated,ABL1(F317L)-phosphorylated, ABL1(II396P)-nonphosphorylated,ABL1(II396P)-phosphorylated, ABL1(M351T)-phosphorylated,ABL1(Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated,ABL1(T315I)-nonphosphorylated, ABL1(T315I)-phosphorylated,ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated,ABL2, ALK(L1196M), AMPK-alpha1, AMPK-alpha2, ANKK1, AURKB, AURKC, AXL,BLK, BMX, BRAF, BRAF(V600E), BRK, BTK, CAMK1, CAMKK1, CAMKK2, CDC2L1,CDC2L2, CDC2L5, CDK11, CDK2, CDK5, CDK7, CDK8, CDKL1, CDKL2, CDKL3,CHEK2, CIT, CLK1, CLK4, CSF1R, CSK, CTK, DDR1, DDR2, DLK, EGFR,EGFR(E746-A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P),EGFR(L747-S752del, P753S), EGFR(L747-T751del, Sins), EGFR(L858R),EGFR(L858R,T790M), EGFR(L861Q), EGFR(S752-1759del), EGFR(T790M), EPHA1,EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB4,EPHB6, ERBB2, ERBB4, ERK8, FAK, FER, FES, FGFR1, FGFR2, FGFR3,FGFR3(G697C), FGFR4, FGR, FLT1, FLT3, FLT3(D835H), FLT3(D835V),FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q),FLT3(N841I), FLT3(R834Q), FLT4, FRK, FYN, GAK, GCN2(Kin.Dom.2, S808G),HCK, HIPK4, HPK1, IKK-alpha, IKK-beta, IRAK1, IRAK4, ITK,JAK1(JH1domain-catalytic), JAK2(JH1domain-catalytic),JAK3(JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT(A829P),KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I),KIT(V559D,V654A), LCK, LIMK1, LIMK2, LOK, LRRK2, LRRK2(G2019S), LTK,LYN, MAK, MAP3K2, MAP3K3, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MEK5, MELK,MERTK, MET, MET(M1250T), MINK, MKNK2, MLK1, MLK2, MLK3, MST1, MST1R,MST2, MUSK, MYLK2, MYO3A, MYO3B, NDR2, NEK1, NEK11, NEK4, NEK5, NEK9,NLK, p38-alpha, p38-beta, p38-delta, p38-gamma, PCTK2, PDGFRA, PDGFRB,PFCDPK1(P. falciparum), PFTAIRE2, PFTK1, PKAC-alpha, PKAC-beta, PYK2,RAF1, RET, RET(M918T), RET(V804L), RET(V804M), RIPK1, RIPK2, RIPK4,ROCK2, RPS6KA4(Kin.Dom.1-N-terminal), RSK2(Kin.Dom.1-N-terminal),RSK3(Kin.DoN-terminal), S6K1, SIK, SLK, SRC, SRMS, SRPK1, STK33, STK35,STK36, SYK, TAK1, TAOK2, TAOK3, TEC, TESK1, TGFBR2, TIE1, TIE2, TNIK,TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TTK, TXK,TYK2(JH1domain-catalytic), TYRO3, ULK3, VEGFR2, YES, YSK4, ZAK, ZAP70 orFGFR(Fibroblast growth factor receptor). In a specific embodiment, thecompound is administered orally, subcutaneously, intravenously orintramuscularly. In a specific embodiment, the compound is administeredchronically.

From the following specific embodiments, examples and claims, otherobjects and advantages of the present disclosure will be obvious tothose skilled in the art.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅ and C₅₋₆ alkyl.

“C₁₋₆ alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 6 carbon atoms, and it isalso referred to herein as “lower alkyl”. In some embodiments, C₁₋₄alkyl is particularly preferred. Examples of alkyl groups include, butare not limited to, methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl(C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄),n-pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl (C₅),3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆).Regardless of whether the alkyl is modified with “substituted”, eachinstance of an alkyl is independently optionally substituted, e.g., forinstance with from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. Appropriate substituents are defined below.

“C₂₋₆ alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 6 carbon atoms, and one or morecarbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon doublebonds). The one or more carbon-carbon double bonds may be internal (suchas in 2-butenyl) or terminal (such as in 1-butenyl). In someembodiments, C₂₋₄ alkenyl is particularly preferred. Examples of alkenylgroups include, but are not limited to, ethenyl (C₂), 1-propenyl (C₃),2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄),pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Regardlessof whether the alkenyl group is modified with “substituted”, eachinstance of an alkenyl group is independently optionally substituted,e.g., for instance with from 1 to 5 substituents, 1 to 3 substituents,or 1 substituent. Appropriate substituents are defined below.

“C₂₋₆ alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 6 carbon atoms, one or morecarbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triplebonds), and optionally one or more carbon-carbon double bonds (e.g., 1,2, or 3 carbon-carbon double bonds). In some embodiments, C₂₋₄ alkynylis particularly preferred. In some embodiments, alkynyl does not containany double bonds. The one or more carbon-carbon triple bonds may beinternal (such as in 2-butynyl) or terminal (such as in 1-butynyl).Examples of the alkynyl groups include, but are not limited to, ethynyl(C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄),pentynyl (C₅), hexynyl (C₆), and the like. Regardless of whether thealkynyl group is modified with “substituted”, each instance of analkynyl group is independently optionally substituted, e.g., forinstance with from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. Appropriate substituents are defined below.

“C₁₋₆ alkylene” refers to a divalent group formed by removing anotherhydrogen of the C₁₋₆ alkyl, and can be a substituted or unsubstitutedalkylene. In some embodiments, C₁₋₄ alkylene is particularly preferred.The unsubstituted alkylene groups include, but are not limited to,methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—),butylene (—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—), hexylene(—CH₂CH₂CH₂CH₂CH₂CH₂—), etc. Examples of substituted alkylene groups,such as those substituted with one or more alkyl (methyl) groups,include, but are not limited to, substituted methylene (—CH(CH₃)—,—C(CH₃)₂—), substituted ethylene (—CH(CH₃)CH₂—, —CH₂CH(CH₃)—,—C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—), substituted propylene (—CH(CH₃)CH₂CH₂—,—CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂—, —CH₂C(CH₃)₂CH₂—,—CH₂CH₂C(CH₃)₂—), etc.

“C₀₋₆ alkylene” includes the chemical bond and C₁₋₆ alkylene groups asdefined above.

“C₁₋₆ alkoxy” refers to the group —OR wherein R is a substituted orunsubstituted C₁₋₆ alkyl. In some embodiments, C₁₋₄ alkoxy group isparticularly preferred. Specific alkoxy groups include, but are notlimited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.

“Halo” or “halogen” means fluorine (F), chlorine (Cl), bromine (Br) andiodine (I). In some embodiments, the halo group is F, —Cl or Br. In someembodiments, the halogen group is F or Cl. In some embodiments, thehalogen group is F.

Thus, “C₁₋₆ haloalkyl” and “C₁₋₆ haloalkoxy” refer to the above “C₁₋₆alkyl” and “C₁₋₆ alkoxy”, which are substituted by one or more halogroups. In some embodiments, C₁₋₄ haloalkyl is particularly preferred,and more preferably C₁₋₂ haloalkyl. In some embodiments, C₁₋₄ haloalkoxygroup is particularly preferred, and more preferably C₁₋₂ haloalkoxygroup. Exemplary haloalkyl groups include, but are not limited to, —CF₃,—CH₂F, —CHF₂, —CHFCH₂F, —CH₂CHF₂, —CF₂CF₃, —CCl₃, —CH₂C₁, —CHCl₂,2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. Exemplary haloalkoxygroups include, but are not limited to: —OCH₂F, —OCHF₂, —OCF₃, and thelike.

“C₃₋₁₀ cycloalkyl” refers to a radical of a non-aromatic cyclichydrocarbon group having from 3 to 10 ring carbon atoms and zeroheteroatoms. In some embodiments, C₃₋₇ cycloalkyl is preferred, C₃₋₆cycloalkyl is particularly preferred, and C₅₋₆ cycloalkyl is morepreferred. Cycloalkyl also includes ring systems wherein the cycloalkylring, as defined above, is fused with one or more aryl or heteroarylgroups wherein the point of attachment is on the cycloalkyl ring, and insuch instances, the number of carbons continue to designate the numberof carbons in the cycloalkyl ring system. Exemplary cycloalkyl groupsinclude, but is not limited to, cyclopropyl (C₃), cyclopropenyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl(C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆),cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇),cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈),bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl(C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀),octahydro-1H-indenyl (C₉), decahydronaphthyl (C₁₀), spiro[4.5]decyl(C₁₀) and the like. Regardless of whether the cycloalkyl is modifiedwith “substituted”, each instance of a cycloalkyl is independentlyoptionally substituted, e.g., for instance with from 1 to 5substituents, 1 to 3 substituents, or 1 substituent. Appropriatesubstituents are defined below.

“3- to 10-membered heterocyclyl” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment may be a carbon or nitrogen atom, as valency permits. Insome embodiments, 3- to 7-membered heterocyclyl is preferred, which is aradical of a 3- to 7-membered non-aromatic ring system having ringcarbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 3- to6-membered heterocyclyl is particularly preferred, which is a radical ofa 3- to 6-membered non-aromatic ring system having ring carbon atoms and1 to 3 ring heteroatoms; 5- to 6-membered heterocyclyl is morepreferred, which is a radical of a 5- to 6-membered non-aromatic ringsystem having ring carbon atoms and 1 to 3 ring heteroatoms.Heterocyclyl also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more aryl or heteroaryl groups,wherein the point of attachment is on the heterocyclyl ring; and in suchinstances, the number of ring members continue to designate the numberof ring members in the heterocyclyl ring system.

Regardless of whether the heterocyclyl group is modified with“substituted”, each instance of an heterocyclyl group is independentlyoptionally substituted, e.g., for instance with from 1 to 5substituents, 1 to 3 substituents, or 1 substituent. Appropriatesubstituents are defined below.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, but are not limited to, azirdinyl, oxiranyl, thiorenyl.Exemplary 4-membered heterocyclyl groups containing one heteroatominclude, but are not limited to, azetidinyl, oxetanyl and thietanyl.Exemplary 5-membered heterocyclyl groups containing one heteroatominclude, but are not limited to, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, but are not limited to, dioxolanyl,oxasulfuranyl, disulfuranyl and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, but are notlimited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include, butare not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl andthianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, but are not limited to, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingthree heteroatoms include, but are not limited to, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, but are not limited to, azepanyl, oxepanyl and thiepanyl.Exemplary 8-membered heterocyclyl groups containing one heteroatominclude, but are not limited to, azocanyl, oxecanyl and thiocanyl.Exemplary 5-membered heterocyclyl groups fused to a C₆ aryl ring (alsoreferred to herein as a 5,6-bicyclic heterocyclic ring) include, but arenot limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary6-membered heterocyclyl groups fused to an C₆ aryl ring (also referredto herein as a 6,6-bicyclic heterocyclic ring) include, but are notlimited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

“C₆₋₁₄ aryl” refers to a radical of a monocyclic or polycyclic (e.g.,bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or14 π electrons shared in a cyclic array) having 6-14 ring carbon atomsand zero heteroatoms. In some embodiments, an aryl group has six ringcarbon atoms (“C₆ aryl”; e.g., phenyl). In some embodiments, an arylgroup has ten ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as1-naphthyl and 2-naphthyl). In some embodiments, an aryl group hasfourteen ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl). In someembodiments, C₆₋₁₀ aryl is particularly preferred, and C₆ aryl is morepreferred. Aryl also includes ring systems wherein the aryl ring, asdefined above, is fused with one or more cycloalkyl or heterocyclylgroups and the radical or point of attachment is on the aryl ring, andin such instances, the number of carbon atoms continue to designate thenumber of carbon atoms in the aryl ring system. Regardless of whetherthe aryl group is modified with “substituted”, each instance of an arylgroup is independently optionally substituted, e.g., for instance withfrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.Appropriate substituents are defined below.

“5- to 10-membered heteroaryl” refers to a radical of a 5-10 memberedmonocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10it electrons shared in a cyclic array) having ring carbon atoms and 1-4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen and sulfur. In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment may be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. Heteroaryl includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more cycloalkyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. In some embodiments, 5- to 6-membered heteroarylgroup is particularly preferred, which is a 5- to 6-membered monocyclicor bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4ring heteroatoms. Regardless of whether the heteroaryl group is modifiedwith “substituted”, each instance of a heteroaryl group is independentlyoptionally substituted, e.g., for instance with from 1 to 5substituents, 1 to 3 substituents, or 1 substituent. Appropriatesubstituents are defined below.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, but are not limited to, pyrrolyl, furanyl and thiophenyl.Exemplary 5-membered heteroaryl groups containing two heteroatomsinclude, but are not limited to, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroarylgroups containing three heteroatoms include, but are not limited to,triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-memberedheteroaryl groups containing four heteroatoms include, but are notlimited to, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining one heteroatom include, but are not limited to, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, but are not limited to, pyridazinyl, pyrimidinyl, andpyrazinyl. Exemplary 6-membered heteroaryl groups containing three orfour heteroatoms include, but are not limited to, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, but are not limited to, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, but are not limited to, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb)) OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃,—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa),—P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, —OP(═O)₂N(R^(bb))₂,—P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂, —P(R^(cc))₃, —OP(R^(cc))₂,—OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), alkyl,perhaloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted by 0, 1,2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O) OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is independently selected from alkyl,perhaloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl, or two R^(aa) groups are joined to form a heterocyclyl orheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted by 0, 1,2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is independently selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, alkyl, perhaloalkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl, or two R^(bb) groups are joined toform a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted by 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is independently selected from hydrogen, alkyl,perhaloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl, or two R^(cc) groups are joined to form a heterocyclyl orheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted by 0, 1,2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is independently selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, alkyl,perhaloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted by 0, 1,2, 3, 4, or 5 R^(gg) groups, or two geminal R^(dd) substituents may bejoined to form ═O or ═S;

each instance of R^(ee) is independently selected from alkyl,perhaloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, andheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted by 0, 1,2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is independently selected from hydrogen, alkyl,perhaloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl andheteroaryl, or two R^(ff) groups are joined to form a heterocyclyl orheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted by 0, 1,2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is independently halogen, —CN, —NO₂, —N₃, —SO₂H,—SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂, —N(C₁₋₆alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃ ⁺X⁻,—N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl),—OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl),—OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl), —NHC(═O)NH(C₁₋₆alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl),—OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl), —C(═NH)NH(C₁₋₆ alkyl),—C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl), —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl), —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl), —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆alkyl)₃-C(═S)N(C₁₋₆ alkyl), C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),—P(═O)(C₁₋₆ alkyl), —OP(═O)(C₁₋₆ alkyl), —OP(═O)(OC₁₋₆ alkyl), C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ carbocyclyl,C₆-C₁₀ aryl, C₃-C₇ heterocyclyl, C₅-C₁₀ heteroaryl; or two geminalR^(gg) substituents may be joined to form ═O or ═S; wherein X⁻ is acounterion.

Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,alkyl, perhaloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl, or two R^(cc) groups attached to a nitrogen atom arejoined to form a heterocyclyl or heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted by 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc) and R^(dd) are as defined above.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptablesalts of the compounds of the present disclosure include those derivedfrom suitable inorganic and organic acids and inorganic and organicbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid. Salts formedby using regular methods used in the art such as ion exchange are alsoincluded. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Pharmaceutically acceptable salts derived from appropriate basesinclude alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Otherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed with counterionssuch as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate,lower alkyl sulfonate, and aryl sulfonate.

“Active metabolite” refers to the pharmacologically active productproduced by the in vivo metabolization of the compound of formula (I) orsalt thereof. The prodrugs and active metabolites of compounds can bedetermined using conventional techniques known or available in the art.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human”, “patient” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat”,“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

“Combination” and related terms mean the simultaneous or sequentialadministration of a therapeutic agent of the present disclosure. Forexample, a compound disclosed herein may be administered simultaneouslyor sequentially with another therapeutic agent in separate unit dosageforms, or together with another therapeutic agent in a single unitdosage form.

SPECIFIC EMBODIMENTS

Compound

Herein, “the compound of the present disclosure” refers to the followingcompound of formula (I) to formula (III) (including the subsets of eachformula, such as the compound of formula (IIIa)), or pharmaceuticallyacceptable salts, enantiomers, diastereomers, racemates, solvates,hydrates, polymorphs, prodrugs or active metabolites thereof.

In one embodiment, the present disclosure relates to the compound offormula (I):

wherein,

X₁, X₂ and X₃ are each independently selected from N or CR_(a);

Y is selected from N, O, S or CR_(a);

Z₁ and Z₂ are each independently selected from N or C, and Z₁ and Z₂ arenot N at the same time;

p, and q represent single bond or double bond, and there is one and onlyone double bond in p and q;

r, and s represent single bond or double bond, and there is one and onlyone double bond in r and s;

provided that when q and r are both single bond, Y is not CR_(a),

provided that when Z₁ is N, X₁, X₂, X₃ and Y are not CR_(a) at the sametime;

each R_(a) is independently selected from H, halogen, cyano, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₀R₁₁, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

ring A is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₁ and R₃ are each independently absent or are H, halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl, wherein the said C₁₋₆ alkylis optionally substituted with one, two or three groups selected fromC₁₋₃ alkyl, hydroxy or C₁₋₃ alkoxy;

R₂ is absent or is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl; wherein the said C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl and 4- to 7-membered heterocyclyl are each optionallysubstituted by one, two or three R₁₄;

wherein R₁ and R₂, or R₂ and R₃ can be combined to form a C₅₋₇cycloalkyl ring or 5- to 7-membered heterocyclyl ring, and wherein thesaid C₅₋₇ cycloalkyl ring or 5- to 7-membered heterocyclyl ring are eachindependently substituted by one, two or three R₁₄;

R₄ is H, halogen, hydroxy, amino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

L is selected from —C(O)NR₉—, —NR₉C(O)—, —NR₉C(O)NR₉— or

ring B is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₅ is absent or is H, halogen, cyano, hydroxy, amino, C₁₋₆ alkyl or C₁₋₆alkoxy;

R₆ and R₇ are absent or are H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl, wherein the said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areoptionally substituted by one, two or three R₁₄;

R₈ is absent or is H or 5- to 7-membered heteroaryl, wherein the said 5-to 7-membered heteroaryl is optionally substituted by one, two or threeR₁₅;

wherein R₅ and R₆, R₆ and R₇, or R₇ and R₈ can be combined to form aC₅₋₇ cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ arylring or 5- to 12-membered heteroaryl ring, and wherein the said C₅₋₇cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ aryl ring and5- to 12-membered heteroaryl ring are each independently substituted byone, two or three R₁₄;

R₉, R₁₀ and R₁₁ are each independently selected from H or C₁₋₃ alkyl;

R₁₂ and R₁₃ are each independently H or C₁₋₆ alkyl; or Ru and R₁₃together with the nitrogen to which they attached form a 4- to7-membered heterocyclyl ring, wherein the formed 4- to 7-memberedheterocyclyl ring is optionally substituted by one, two or three R₁₅;

each R₁₄ is independently selected from halogen, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, —NR₁₆R₁₇, —C(O)NR₁₈R₁₉, C₃₋₇ cycloalkyl or 3- to7-membered heterocyclyl, wherein the said C₃₋₇ cycloalkyl and 3- to7-membered heterocyclyl are optionally substituted by one, two or threeR₁₅;

each R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl,C₁₋₃ alkoxy or —NR₂₀R₂₁;

R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ and R₂₁ are each independently H or C₁₋₃ alkyl.

In one embodiment of general formula (I), X₁, X₂ and X₃ are eachindependently selected from N or CH, Y is selected from N or CH, Z₁ andZ₂ are each independently N or C, and at least two of X₁, X₂, X₃, Y, Z₁and Z₂ are N.

In one alternative embodiment,

has the structure of

wherein X₁, X₂, X₃ and Y are each independently selected from N or CH,and X₁, X₂, X₃ and Y are not all CH; in another alternative embodiment,

is selected from the group of the following structures:

In another alternative embodiment,

has the structure of

wherein X₁, X₂, X₃ and Y are each independently selected from N or CH.

In another alternative embodiment

has the structure of

wherein X₁, X₂, X₃ and Y are each independently selected from N or CH.

In one embodiment of general formula (I), R₁ and R₃ are eachindependently selected from H, halogen, —NH₂, C₁₋₆ haloalkyl, or C₁₋₆alkyl, and wherein the said C₁₋₆ alkyl is optionally substituted by onehydroxy. In one alternative embodiment, R₁ and R₃ are each independentlyselected from H, F, —NH₂ or —CF₃. In another alternative embodiment, R₁and R₃ are C₁₋₃ alkyl optionally substituted by hydroxy.

In one embodiment of general formula (I), R₂ is selected from C₁₋₆alkyl, C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl, wherein thesaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areeach optionally substituted by one or two R₁₄. In one alternativeembodiment, R₂ is selected from methyl, ethyl, isopropyl, —(CH₂)₂OCH₃,—(CH₂)₃OCH₃, —(CH₂)₂N(CH₃)₂, —(CH₂)₃N(CH₃)₂, piperidinyl orN-methylpiperidinyl.

In one embodiment of general formula (I), R₁ and R₂, or R₂ and R₃ can becombined to form a 5- to 6-membered heterocyclyl ring, and wherein thesaid 5- to 6-membered heterocyclyl ring is each independentlysubstituted by one, two or three R₁₄. In one alternative embodiment, R₁and R₂, or R₂ and R₃ can be combined to form a piperidine ring or apiperazine ring, wherein the said piperidine ring or piperazine ring isoptionally substituted by one or two R₁₄.

In one embodiment of general formula (I), R₄ is selected from H, F ormethyl. In one alternative embodiment, R₄ is methyl.

In one embodiment of general formula (I), L is selected from —C(O)NH—,—NHC(O)—, —NHC(O)NH— or

In one alternative embodiment, L is —C(O)NH—; in another alternativeembodiment, L is —NHC(O)—.

In one embodiment of general formula (I), ring B is selected from C₆₋₁₀aryl ring or 5- to 12-membered heteroaryl ring. In one alternativeembodiment, ring B is selected from benzene, pyridine, isoxazole,quinoline or benzothiazole.

One embodiment of the general formula (I) refers to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (I), which has the formula (I-1):

wherein,

X₁, X₂, X₃ and Y are each independently selected from N or CH, and atleast one of X₁, X₂, X₃ and Y is N;

ring A is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₁ and R₃ are each independently absent or are H, halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl, wherein the C₁₋₆ alkyl isoptionally substituted by one, two or three groups selected from C₁₋₃alkyl, hydroxy or C₁₋₃ alkoxy;

R₂ is absent or is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl; wherein the said C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl and 4- to 7-membered heterocyclyl are each optionallysubstituted by one, two or three R₁₄;

wherein R₁ and R₂ or R₂ and R₃ can be combined to form a C₅₋₇ cycloalkylring or 5- to 7-membered heterocyclyl ring, and wherein the said C₅₋₇cycloalkyl ring and 5- to 7-membered heterocyclyl ring are eachindependently substituted by one, two or three R₁₄;

R₄ is H, halogen, hydroxy, amino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

L is selected from —C(O)NR₉—, —NR₉C(O)—, —NR₉C(O)NR₉— or

ring B is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₅ is absent or is H, halogen, cyano, hydroxy, amino, C₁₋₆ alkyl or C₁₋₆alkoxy;

R₆ and R₇ are absent or are H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl, wherein the said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areoptionally substituted by one, two or three R₁₄;

R₈ is absent or is H or 5- to 7-membered heteroaryl, wherein the said 5-to 7-membered heteroaryl is optionally substituted by one, two or threeR₁₅;

wherein R₅ and R₆, R₆ and R₇, or R₇ and R₈ can be combined to form aC₅₋₇ cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ arylring or 5- to 12-membered heteroaryl ring, and wherein the said C₅₋₇cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ aryl ring and5- to 12-membered heteroaryl ring are each independently substituted byone, two or three R₁₄;

R₁₂ and R₁₃ are each independently H or C₁₋₆ alkyl; or R₁₂ and R₁₃together with the nitrogen to which they attached form a 4- to7-membered heterocyclyl ring, wherein the formed 4- to 7-memberedheterocyclyl ring is optionally substituted by one, two or three R₁₅;

each R₁₄ is independently selected from halogen, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, —NR₁₆R₁₇, —C(O)NR₁₈R₁₉, C₃₋₇ cycloalkyl or 3- to7-membered heterocyclyl, wherein the said C₃₋₇ cycloalkyl and 3- to7-membered heterocyclyl are optionally substituted by one, two or threeR₁₅;

each R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl,C₁₋₃ alkoxy or —NR₂₀R₂₁;

R₉, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ and R₂₁ are each independently H or C₁₋₃alkyl.

In one embodiment of general formula (I-1), R₁ and R₃ are eachindependently selected from H, halogen, —NH₂, C₁₋₆ haloalkyl or C₁₋₆alkyl, and wherein the said C₁₋₆ alkyl is optionally substituted by onehydroxy. In one alternative embodiment, R₁ and R₃ are each independentlyselected from H, F, —NH₂ or —CF3. In another alternative embodiment, R₁and R₃ are C₁₋₃ alkyl optionally substituted by hydroxy.

In one embodiment of general formula (I-1), R₂ is selected from C₁₋₆alkyl, C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl, wherein thesaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areeach optionally substituted by one or two R₁₄. In one alternativeembodiment, R₂ is selected from methyl, ethyl, isopropyl, —(CH₂)₂OCH₃,—(CH₂)₃OCH₃, —(CH₂)₂N(CH₃)₂, —(CH₂)₃N(CH₃)₂, piperidinyl orN-methylpiperidinyl.

In one embodiment of general formula (I-1), R₁ and R₂, or R₂ and R₃ canbe combined to form a 5- to 6-membered heterocyclyl ring, and whereinthe said 5- to 6-membered heterocyclyl ring is each independentlysubstituted by one, two or three R₁₄. In one alternative embodiment, R₁and R₂, or R₂ and R₃ can be combined to form a piperidine ring or apiperazine ring, wherein the said piperidine ring or piperazine ring isoptionally substituted by one or two R₁₄.

In one embodiment of general formula (I-1), R₄ is selected from H, F ormethyl. In one alternative embodiment, R₄ is methyl.

In one embodiment of general formula (I-1), L is selected from —C(O)NH—,—NHC(O)—, —NHC(O)NH— or

In one alternative embodiment, L is —C(O)NH—; in another alternativeembodiment, L is —NHC(O)—.

In one embodiment of general formula (I-1), ring B is selected fromC₆₋₁₀ aryl ring or 5- to 12-membered heteroaryl ring. In one alternativeembodiment, ring B is selected from benzene, pyridine, isoxazole,quinoline or benzothiazole.

One embodiment of the general formula (I) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (I), which has formula (Ia):

wherein,

U₁ is selected from CH or N;

U₂ is selected from CR₈ or N;

U₃ is selected from CR₇ or N.

In one embodiment of general formula (Ia), R₅ is selected from H, F, Clor methyl.

In one embodiment of general formula (Ia), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In one embodiment of general formula (Ia), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, Cl or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

In one embodiment of general formula (Ia), R₈ is selected from H orimidazolyl substituted with a C₁₋₃ alkyl.

One embodiment of the general formula (I) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound ofthe formula (I), which has the formula (Ib):

In one embodiment of general formula (Ib), R₅ is selected from H, F, Clor methyl.

In one embodiment of general formula (Ib), R₆ is selected from H, F,methoxy, trifluoromethyl or C₁₋₆ alkyl optionally substituted by oneR₁₄. In one alternative embodiment, R₆ is tert-butyl. In anotheralternative embodiment, R₆ is 2-trifluoromethylprop-2-yl.

One embodiment of the general formula (I) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound ofthe formula (I), which has the formula (Ic):

In one embodiment of general formula (Ic), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In one embodiment of general formula (Ic), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl, orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

One embodiment of the general formula (I) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (I), which has the formula (Id):

In an embodiment of the general formula (Id), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In an embodiment of the general formula (Id), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

In one embodiment, the present disclosure relates to a compound offormula (II) or a pharmaceutically acceptable salt thereof:

wherein,

X₁, X₂ and X₃ are each independently selected from N or CR_(a);

Y is selected from N, O, S or CR_(a);

Z₁ and Z₂ are each independently selected from N or C, and Z₁ and Z₂ arenot N at the same time;

p, and q represent single bond or double bond, and there is one and onlyone double bond in p and q;

r, and s represent single bond or double bond, and there is one and onlyone double bond in r and s;

provided that when q and r are both single bond, Y is not CR_(a),

provided that when Z₁ is N, X₁, X₂, X₃ and Y are not CR_(a) at the sametime;

each R_(a) is independently selected from H, halogen, cyano, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₀R₁₁, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

W and V are each independently selected from CR₁ or N;

provided that one of W and V is N, and W and V are not N at the sametime;

R₁ and R₃ are each independently absent or are H, halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl, wherein the C₁₋₆ alkyl isoptionally substituted by one, two or three groups selected from C₁₋₃alkyl, hydroxy or C₁₋₃ alkoxy;

R₂ is absent or is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl; wherein the said C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl and 4- to 7-membered heterocyclyl are each optionallysubstituted by one, two or three R₁₄;

wherein R₁ and R₂, or R₂ and R₃ can be combined to form a C₅₋₇cycloalkyl ring or 5- to 7-membered heterocyclyl ring, and wherein thesaid C₅₋₇ cycloalkyl ring and 5- to 7-membered heterocyclyl ring areeach independently substituted by one, two or three R₁₄;

R₄ is H, halogen, hydroxy, amino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

L is selected from —C(O)NR₉—, —NR₉C(O)—, —NR₉C(O)NR₉— or

ring B is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₅ is absent or is H, halogen, cyano, hydroxy, amino, C₁₋₆ alkyl or C₁₋₆alkoxy;

R₆ and R₇ are absent or are H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl, wherein the said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areoptionally substituted by one, two or three R₁₄;

R₈ is absent or is H or 5- to 7-membered heteroaryl, wherein the said 5-to 7-membered heteroaryl is optionally substituted by one, two or threeR₁₅;

wherein R₅ and R₆, R₆ and R₇, or R₇ and R₈ can be combined to form aC₅₋₇ cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ arylring or 5- to 12-membered heteroaryl ring, and wherein the said C₅₋₇cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ aryl ring and5- to 12-membered heteroaryl ring are each independently substituted byone, two or three R₁₄;

R₉, R₁₀ and R₁₁ are each independently selected from H or C₁₋₃ alkyl;

R₁₂ and R₁₃ are each independently H or C₁₋₆ alkyl; or Ru and R₁₃together with the nitrogen to which they attached form a 4- to7-membered heterocyclyl ring, wherein the formed 4- to 7-memberedheterocyclyl ring is optionally substituted by one, two or three R₁₅;

each R₁₄ is independently selected from halogen, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, —NR₁₆R₁₇, —C(O)NR₁₈R₁₉, C₃₋₇ cycloalkyl or 3- to7-membered heterocyclyl, wherein the said C₃₋₇ cycloalkyl and 3- to7-membered heterocyclyl are optionally substituted by one, two or threeR₁₅;

each R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl,C₁₋₃ alkoxy or —NR₂₀R₂₁;

R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ and R₂₁ are each independently H or C₁₋₃ alkyl.

In one embodiment of general formula (II), X₁, X₂ and X₃ are eachindependently selected from N or CH, Y is selected from N or CH, Z₁ andZ₂ are each independently N or C, and at least two of X₁, X₂, X₃, Y, Z₁and Z₂ are N.

In one alternative embodiment,

has the following structure

wherein X₁, X₂, X₃ and Y are each independently selected from N or CH,and X₁, X₂, X₃ and Y are not all CH; in another alternative embodiment,

is selected from the group with the following structures:

In another alternative embodiment,

has the following structure

wherein X₁, X₂, X₃ and Y are each independently selected from N or CH.

In another alternative embodiment

has the following structure

wherein X₁, X₂, X₃ and Y are each independently selected from N or CH.

In one embodiment of general formula (II), R₁ and R₃ are eachindependently selected from H, halogen, —NH₂, C₁₋₆ haloalkyl or C₁₋₆alkyl, and wherein the C₁₋₆ alkyl is optionally substituted by onehydroxy. In one alternative embodiment, R₁ and R₃ are each independentlyselected from H, F, —NH₂ or —CF₃. In another alternative embodiment, R₁and R₃ are C₁₋₃ alkyl optionally substituted by hydroxy.

In one embodiment of general formula (II), R₂ is selected from C₁₋₆alkyl, C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl, wherein thesaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areeach optionally substituted by one or two R₁₄. In one alternativeembodiment, R₂ is selected from methyl, ethyl, isopropyl, —(CH₂)₂OCH₃,—(CH₂)₃OCH₃, —(CH₂)₂N(CH₃)₂, —(CH₂)₃N(CH₃)₂, piperidinyl orN-methylpiperidinyl.

In one embodiment of general formula (II), R₁ and R₂, or R₂ and R₃ canbe combined to form a 5- to 6-membered heterocyclyl ring, and whereinthe said 5- to 6-membered heterocyclyl ring is each independentlysubstituted by one, two or three R₁₄. In one alternative embodiment, R₁and R₂, or R₂ and R₃ can be combined to form a piperidine ring or apiperazine ring, wherein the said piperidine ring or piperazine ring isoptionally substituted by one or two R₁₄.

In one embodiment of general formula (II), R₄ is selected from H, F ormethyl. In one alternative embodiment, R₄ is methyl.

In one embodiment of general formula (II), L is selected from —C(O)NH—,—NHC(O)—, —NHC(O)NH— or

In one alternative embodiment, L is —C(O)NH—; in another alternativeembodiment, L is —NHC(O)—.

In one embodiment of general formula (II), ring B is selected from C₆₋₁₀aryl ring or 5- to 12-membered heteroaryl ring. In one alternativeembodiment, ring B is selected from benzene, pyridine, isoxazole,quinoline or benzothiazole.

One embodiment of the general formula (II) relates to a compound orpharmaceutically acceptable salt of any embodiment of the compound offormula (II), which has the formula (II-1):

wherein,

W and V are each independently selected from CR₁ or N;

provided that when one of W and V is N, W and V are not N at the sametime;

X₁, X₂, X₃ and Y are each independently selected from N or CH, and atleast one of X₁, X₂, X₃ and Y is N;

ring A is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₁ and R₃ are each independently absent or are H, halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl, wherein the C₁₋₆ alkyl isoptionally substituted by one, two or three groups selected from C₁₋₃alkyl, hydroxy or C₁₋₃ alkoxy;

R₂ is absent or is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl; wherein the said C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl and 4- to 7-membered heterocyclyl are each optionallysubstituted by one, two or three R₁₄;

wherein R₁ and R₂, or R₂ and R₃ can be combined to form a C₅₋₇cycloalkyl ring or 5- to 7-membered heterocyclyl ring, and wherein thesaid C₅₋₇ cycloalkyl ring and 5- to 7-membered heterocyclyl ring areeach independently substituted by one, two or three R₁₄;

R₄ is H, halogen, hydroxy, amino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

L is selected from —C(O)NR₉—, —NR₉C(O)—, —NR₉C(O)NR₉— or

ring B is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₅ is absent or is H, halogen, cyano, hydroxy, amino, C₁₋₆ alkyl or C₁₋₆alkoxy;

R₆ and R₇ are absent or are H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl, wherein the said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areoptionally substituted by one, two or three R₁₄;

R₈ is absent or is H or 5- to 7-membered heteroaryl, wherein the said 5-to 7-membered heteroaryl is optionally substituted by one, two or threeR₁₅;

wherein R₅ and R₆, R₆ and R₇, or R₇ and R₈ can be combined to form aC₅₋₇ cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ arylring or 5- to 12-membered heteroaryl ring, and wherein the said C₅₋₇cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ aryl ring and5- to 12-membered heteroaryl ring are each independently substituted byone, two or three R₁₄;

R₁₂ and R₁₃ are each independently H or C₁₋₆ alkyl; or R₁₂ and R₁₃together with the nitrogen to which they attached form a 4- to7-membered heterocyclyl ring, wherein the formed 4- to 7-memberedheterocyclyl ring is optionally substituted by one, two or three R₁₅;

each R₁₄ is independently selected from halogen, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, —NR₁₆R₁₇, —C(O)NR₁₈R₁₉, C₃₋₇ cycloalkyl or 3- to7-membered heterocyclyl, wherein the said C₃₋₇ cycloalkyl and 3- to7-membered heterocyclyl are optionally substituted by one, two or threeR₁₅;

each R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl,C₁₋₃ alkoxy or —NR₂₀R₂₁;

R₉, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ and R₂₁ are each independently H or C₁₋₃alkyl.

In one embodiment of general formula (II-1), R₁ and R₃ are eachindependently selected from H, halogen, —NH₂, C₁₋₆ haloalkyl or C₁₋₆alkyl, and wherein the said C₁₋₆ alkyl is optionally substituted by onehydroxy. In one alternative embodiment, R₁ and R₃ are each independentlyselected from H, F, —NH₂ or —CF₃. In another alternative embodiment, R₁and R₃ are C₁₋₃ alkyl optionally substituted by hydroxy.

In one embodiment of general formula (II-1), R₂ is selected from C₁₋₆alkyl, C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl, wherein thesaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areeach optionally substituted by one or two R₁₄. In one alternativeembodiment, R₂ is selected from methyl, ethyl, isopropyl, —(CH₂)₂OCH₃,—(CH₂)₃OCH₃, —(CH₂)₂N(CH₃)₂, —(CH₂)₃N(CH₃)₂, piperidinyl orN-methylpiperidinyl.

In one embodiment of general formula (II-1), R₁ and R₂, or R₂ and R₃ canbe combined to form a 5- to 6-membered heterocyclyl ring, and whereinthe said C₅₋₇ cycloalkyl ring and 5- to 7-membered heterocyclyl ring areeach independently substituted by one, two or three R₁₄. In onealternative embodiment, R₁ and R₂, or R₂ and R₃ can be combined to forma piperidine ring or a piperazine ring, wherein the said piperidine ringor piperazine ring is optionally substituted by one or two R₁₄.

In one embodiment of general formula (II-1), R₄ is selected from H, F ormethyl. In one alternative embodiment, R₄ is methyl.

In one embodiment of general formula (II-1), L is selected from—C(O)NH—, —NHC(O)—, —NHC(O)NH— or

In one alternative embodiment, L is —C(O)NH—; in another alternativeembodiment, L is —NHC(O)—.

In one embodiment of general formula (II-1), ring B is selected fromC₆₋₁₀ aryl ring or 5- to 12-membered heteroaryl ring. In one alternativeembodiment, ring B is selected from benzene, pyridine, isoxazole,quinoline or benzothiazole.

One embodiment of the general formula (II) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (II), which has the formula (IIa):

wherein,

U₁ is selected from CH or N;

U₂ is selected from CR₈ or N;

U₃ is selected from CR₇ or N.

In one embodiment of general formula (IIa), R₅ is selected from H, F, Clor methyl.

In one embodiment of general formula (IIa), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In one embodiment of general formula (IIa), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

In one embodiment of general formula (IIa), R₈ is selected from H orimidazolyl substituted with a C₁₋₃ alkyl.

One embodiment of the general formula (II) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (II), which has the formula (IIb):

In one embodiment of general formula (IIb), R₅ is selected from H, F, Clor methyl.

In one embodiment of general formula (IIb), R₆ is selected from H, F,methoxy, trifluoromethyl or C₁₋₆ alkyl optionally substituted by oneR₁₀. In one alternative embodiment, R₆ is tert-butyl. In anotheralternative embodiment, R₆ is 2-trifluoromethylprop-2-yl.

One embodiment of the general formula (II) relates to a compound of anyembodiment of the compound of formula (II) or a pharmaceuticallyacceptable salt, which has the formula (IIc):

In one embodiment of general formula (IIc), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In one embodiment of general formula (IIc), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₀. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

One embodiment of the general formula (II) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (II), which has the formula (IId):

In one embodiment of general formula (IId), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In one embodiment of general formula (IId), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, Cl or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

In one embodiment, the present disclosure relates to a compound offormula (III) or a pharmaceutically acceptable salt thereof:

X₁, X₂ and X₃ are each independently selected from N or CR_(a);

Y is selected from N, O, S or CR_(a);

Z₁ and Z₂ are each independently selected from N or C, Z1 and Z2 are notN at the same time;

p, and q represent single bond or double bond, and there is one and onlyone double bond in p and q;

r, and s represent single bond or double bond, and there is one and onlyone double bond in r and s;

provided that when q and r are both single bond, Y is not CR_(a),

provided that when Z₁ is N, X₁, X₂, X₃ and Y are not CR_(a) at the sametime;

each R_(a) is independently selected from H, halogen, cyano, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₀R₁₁, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

ring A is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₁ and R₃ are each independently absent or are H, halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl, wherein the C₁₋₆ alkyl isoptionally substituted by one, two or three groups selected from C₁₋₃alkyl, hydroxy or C₁₋₃ alkoxy;

R₂ is absent or is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl; wherein the said C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl and 4- to 7-membered heterocyclyl are each optionallysubstituted by one, two or three R₁₄;

wherein R₁ and R₂ can be combined to form a C₅₋₇ cycloalkyl ring or 5-to 7-membered heterocyclyl ring, and wherein the said C₅₋₇ cycloalkylring and 5- to 7-membered heterocyclyl ring are each independentlysubstituted by one, two or three R₁₄;

R₄ is H, halogen, hydroxy, amino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

L is selected from —C(O)NR₉—, —NR₉C(O)—, —NR₉C(O)NR₉— or

ring B is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₅ is absent or is H, halogen, cyano, hydroxy, amino, C₁₋₆ alkyl or C₁₋₆alkoxy;

R₆ and R₇ are absent or are H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl, wherein the said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areoptionally substituted by one, two or three R₁₄;

R₈ is absent or is H or 5- to 7-membered heteroaryl, wherein the said 5-to 7-membered heteroaryl is optionally substituted by one, two or threeR₁₅;

wherein R₅ and R₆, R₆ and R₇, or R₇ and R₈ can be combined to form aC₅₋₇ cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ arylring or 5- to 12-membered heteroaryl ring, and wherein the said C₅₋₇cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ aryl ring and5- to 12-membered heteroaryl ring are each independently substituted byone, two or three R₁₄;

R₉, R₁₀ and R₁₁ are each independently selected from H or C₁₋₃ alkyl;

R₁₂ and R₁₃ are each independently H or C₁₋₆ alkyl; or Ru and R₁₃together with the nitrogen to which they attached form a 4- to7-membered heterocyclyl ring, wherein the formed 4- to 7-memberedheterocyclyl ring is optionally substituted by one, two or three R₁₅;

each R₁₄ is independently selected from halogen, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, —NR₁₆R₁₇, —C(O)NR₁₈R₁₉, C₃₋₇ cycloalkyl or 3- to7-membered heterocyclyl, wherein the said C₃₋₇ cycloalkyl and 3- to7-membered heterocyclyl are optionally substituted by one, two or threeR₁₅;

each R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl,C₁₋₃ alkoxy or —NR₂₀R₂₁;

R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ and R₂₁ are each independently H or C₁₋₃ alkyl.

In one embodiment of general formula (III), X₁, X₂ and X₃ are eachindependently selected from N or CH, Y is selected from N or CH, Z₁ andZ₂ are each independently N or C, and at least two of X₁, X₂, X₃, Y, Z₁and Z₂ are N.

In one alternative embodiment,

has the following structure

wherein X₁, X₂, X₃ and Y are each independently selected from N or CH,and X₁, X₂, X₃ and Y are not all CH; in another alternative embodiment,

is selected from the group with the following structures:

In another alternative embodiment,

has the following structure

wherein X₁, X₂, X₃ and Y are each independently selected from N or CH.

In another alternative embodiment

has the following structure

wherein X₁, X₂, X₃ and Y are each independently selected from N or CH.

In one embodiment of general formula (III), R₁ and R₃ are eachindependently selected from H, halogen, —NH₂, C₁₋₆ haloalkyl or C₁₋₆alkyl, and wherein the said C₁₋₆ alkyl is optionally substituted by onehydroxy. In one alternative embodiment, R₁ and R₃ are each independentlyselected from H, F, —NH₂ or —CF₃. In another alternative embodiment, R₁and R₃ are C₁₋₃ alkyl optionally substituted by hydroxy.

In one embodiment of general formula (III), R₂ is selected from C₁₋₆alkyl, C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl, wherein thesaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areeach optionally substituted by one or two R₁₄. In one alternativeembodiment, R₂ is selected from methyl, ethyl, isopropyl, —(CH₂)₂OCH₃,—(CH₂)₃OCH₃, —(CH₂)₂N(CH₃)₂, —(CH₂)₃N(CH₃)₂, piperidinyl,N-methylpiperidinyl.

In one embodiment of general formula (III), R₁ and R₂ can be combined toform a 5- to 6-membered heterocyclyl ring, and wherein the said 5- to6-membered heterocyclyl ring is each independently substituted by one,two or three R₁₄. In one alternative embodiment, R₁ and R₂ can becombined to form a piperidine ring or a piperazine ring, wherein thesaid piperidine ring or piperazine ring is optionally substituted by oneor two R₁₄.

In one embodiment of general formula (III), R₄ is selected from H, F ormethyl. In one alternative embodiment, R₄ is methyl.

In one embodiment of general formula (III), L is selected from —C(O)NH—,—NHC(O)—, —NHC(O)NH— or

In one alternative embodiment, L is —C(O)NH—; in another alternativeembodiment, L is —NHC(O)—.

In one embodiment of general formula (III), ring B is selected fromC₆₋₁₀ aryl ring or 5- to 12-membered heteroaryl ring. In one alternativeembodiment, ring B is selected from benzene, pyridine, isoxazole,quinoline or benzothiazole.

One embodiment of the general formula (III) relates to a compound of anyembodiment of the compound of formula (III) or a pharmaceuticallyacceptable salt, which has the formula (III-1):

wherein,

X₁, X₂, X₃ and Y are each independently selected from N or CH, and atleast one of X₁, X₂, X₃ and Y is N;

ring A is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₁ and R₃ are each independently absent or are H, halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl, wherein the C₁₋₆ alkyl isoptionally substituted by one, two or three groups selected from C₁₋₃alkyl, hydroxy or C₁₋₃ alkoxy;

R₂ is absent or is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl; wherein the said C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl and 4- to 7-membered heterocyclyl are each optionallysubstituted by one, two or three R₁₄;

wherein R₁ and R₂, or R₂ and R₃ can be combined to form a C₅₋₇cycloalkyl ring or 5- to 7-membered heterocyclyl ring, and wherein thesaid C₅₋₇ cycloalkyl ring and 5- to 7-membered heterocyclyl ring areeach independently substituted by one, two or three R₁₄;

R₄ is H, halogen, hydroxy, amino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

L is selected from —C(O)NR₉—, —NR₉C(O)—, —NR₉C(O)NR₉— or

ring B is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₅ is absent or is H, halogen, cyano, hydroxy, amino, C₁₋₆ alkyl or C₁₋₆alkoxy;

R₆ and R₇ are absent or are H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl, wherein the said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areoptionally substituted by one, two or three R₁₄;

R₈ is absent or is H or 5- to 7-membered heteroaryl, wherein the said 5-to 7-membered heteroaryl is optionally substituted by one, two or threeR₁₅;

wherein R₅ and R₆, R₆ and R₇, or R₇ and R₈ can be combined to form aC₅₋₇ cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ arylring or 5- to 12-membered heteroaryl ring, and wherein the said C₅₋₇cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ aryl ring and5- to 12-membered heteroaryl ring are each independently substituted byone, two or three R₁₄;

R₁₂ and R₁₃ are each independently H or C₁₋₆ alkyl; or R₁₂ and R₁₃together with the nitrogen to which they attached form a 4- to7-membered heterocyclyl ring, wherein the formed 4- to 7-memberedheterocyclyl ring is optionally substituted by one, two or three R₁₅;

each R₁₄ is independently selected from halogen, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, —NR₁₆R₁₇, —C(O)NR₁₈R₁₉, C₃₋₇ cycloalkyl or 3- to7-membered heterocyclyl, wherein the said C₃₋₇ cycloalkyl and 3- to7-membered heterocyclyl are optionally substituted by one, two or threeR₁₅;

each R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl,C₁₋₃ alkoxy or —NR₂₀R₂₁;

R₉, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ and R₂₁ are each independently H or C₁₋₃alkyl.

In one embodiment of general formula (III-1), R₁ and R₃ are eachindependently selected from H, halogen, —NH₂, C₁₋₆ haloalkyl or C₁₋₆alkyl, and wherein the said C₁₋₆ alkyl is optionally substituted by onehydroxy. In one alternative embodiment, R₁ and R₃ are each independentlyselected from H, F, —NH₂ or —CF₃. In another alternative embodiment, R₁and R₃ are C₁₋₃ alkyl optionally substituted by hydroxy.

In one embodiment of general formula (III-1), R₂ is selected from C₁₋₆alkyl, C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl, wherein thesaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areeach optionally substituted by one or two R₁₄. In one alternativeembodiment, R₂ is selected from methyl, ethyl, isopropyl, —(CH₂)₂OCH₃,—(CH₂)₃OCH₃, —(CH₂)₂N(CH₃)₂, —(CH₂)₃N(CH₃)₂, piperidinyl orN-methylpiperidinyl.

In one embodiment of general formula (III-1), R₁ and R₂ can be combinedto form a 5- to 6-membered heterocyclyl ring, and wherein the said 5- to6-membered heterocyclyl ring is each independently substituted by one,two or three R₁₄. In one alternative embodiment, R₁ and R₂ can becombined to form a piperidine ring or a piperazine ring, wherein thesaid piperidine ring and piperazine ring is optionally substituted byone or two R₁₄.

In one embodiment of general formula (III-1), R₄ is selected from H, For methyl. In one alternative embodiment, R₄ is methyl.

In one embodiment of general formula (III-1), L is selected from—C(O)NH—, —NHC(O)—, —NHC(O)NH— or

In one alternative embodiment, L is —C(O)NH—; in another alternativeembodiment, L is —NHC(O)—.

In one embodiment of general formula (III-1), ring B is selected fromC₆₋₁₀ aryl ring or 5- to 12-membered heteroaryl ring. In one alternativeembodiment, ring B is selected from benzene, pyridine, isoxazole,quinoline or benzothiazole.

One embodiment of the general formula (III) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (III), which has the formula (IIIa):

wherein,

U₁ is selected from CH or N;

U₂ is selected from CR₈ or N;

U₃ is selected from CR₇ or N.

In one embodiment of general formula (IIIa), R₅ is selected from H, F,Cl or methyl.

In one embodiment of general formula (IIIa), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In one embodiment of general formula (IIIa), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

In one embodiment of general formula (IIIa), R₈ is selected from H,imidazolyl substituted with a C₁₋₃ alkyl.

One embodiment of the general formula (III) relates to a compound of anyembodiment of the compound of formula (III) or a pharmaceuticallyacceptable salt, which has the formula (IIIa-1):

wherein,

X₁ and X₃ are each independently selected from N or CH, and at least oneof X₁ and X₃ is N;

R₂ is selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl or 4- to 7-memberedheterocyclyl; wherein the said C₁₋₆ alkyl, C₃₋₇ cycloalkyl and 4- to7-membered heterocyclyl are each optionally substituted by one or twoR₁₄;

R₄ is selected from H, halogen or C₁₋₆ alkyl;

L is selected from —C(O)NH—, —NHC(O)—, —NHC(O)NH— or

R₆ is selected from H, halogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl;

U₁ is selected from CH or N;

U₂ is selected from CR₈ or N;

U₃ is selected from CR₇ or N;

R₇ is selected from H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl, wherein the said C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-memberedheterocyclyl are optionally substituted by one, two or three R₁₄;

R₈ is selected from H or 5- to 7-membered heteroaryl, wherein the said5- to 7-membered heteroaryl is optionally substituted by one, two orthree R₁₅;

each R₁₄ is independently selected from halogen, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl or 3- to 7-membered heterocyclyl,wherein the said C₃₋₇ cycloalkyl and 3- to 7-membered heterocyclyl areoptionally substituted by one, two or three R₁₅;

each R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl orC₁₋₃ alkoxy.

In one embodiment of general formula (IIIa-1), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In one embodiment of general formula (IIIa-1), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

In one embodiment of general formula (IIIa-1), R₈ is selected from H orimidazolyl substituted with a C₁₋₃ alkyl.

One embodiment of the general formula (III) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (III), which has the formula (IIIa-2):

wherein,

X₁ and X₃ are each independently selected from N or CH, and at least oneof X₁ and X₃ is N;

R₂ is selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl or 4- to 7-memberedheterocyclyl; wherein the said C₁₋₆ alkyl, C₃₋₇ cycloalkyl and 4- to7-membered heterocyclyl are each optionally substituted by one or twoR₁₄;

R₄ is selected from H, halogen or C₁₋₆ alkyl;

L is selected from —C(O)NH—, —NHC(O)—, —NHC(O)NH— or

R₇ is selected from H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl, wherein the said C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-memberedheterocyclyl are optionally substituted by one, two or three R₁₄;

R₈ is selected from H or 5- to 7-membered heteroaryl, wherein the said5- to 7-membered heteroaryl is optionally substituted by one, two orthree R₁₅;

each R₁₄ is independently selected from halogen, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl or 3- to 7-membered heterocyclyl,wherein the said C₃₋₇ cycloalkyl and 3- to 7-membered heterocyclyl areoptionally substituted by one, two or three R₁₅;

each R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl orC₁₋₃ alkoxy.

In one embodiment of general formula (IIIa-2), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

In one embodiment of general formula (IIIa-2), R₈ is selected from H orimidazolyl substituted with a C₁₋₃ alkyl.

One embodiment of the general formula (III) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (III), which has the formula (IIIa-3):

wherein,

X₁ and X₃ are each independently selected from N or CH, and at least oneof X₁ and X₃ is N;

L is selected from —C(O)NH—, —NHC(O)—, —NHC(O)NH— or

R₇ is selected from H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl, wherein the said C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-memberedheterocyclyl are optionally substituted by one, two or three R₁₄;

R₈ is selected from H or 5- to 7-membered heteroaryl, wherein the said5- to 7-membered heteroaryl is optionally substituted by one, two orthree R₁₅;

each R₁₄ is independently selected from halogen, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl or 3- to 7-membered heterocyclyl,wherein the said C₃₋₇ cycloalkyl and 3- to 7-membered heterocyclyl areoptionally substituted by one, two or three R₁₅;

each R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl orC₁₋₃ alkoxy.

In one embodiment of general formula (IIIa-3), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

In one embodiment of general formula (IIIa-3), R₈ is selected from H orimidazolyl substituted with a C₁₋₃ alkyl.

One embodiment of the general formula (III) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (III), which has the formula (IIIb):

In one embodiment of general formula (IIIb), R₅ is selected from H, F,Cl or methyl.

In one embodiment of general formula (IIIb), R₆ is selected from H, F,methoxy, trifluoromethyl or C₁₋₆ alkyl optionally substituted by oneR₁₄. In one alternative embodiment, R₆ is tert-butyl. In anotheralternative embodiment, R₆ is 2-trifluoromethylprop-2-yl.

One embodiment of the general formula (III) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (III), which has the formula (IIIc):

In one embodiment of general formula (IIIc), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In one embodiment of general formula (IIIc), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

One embodiment of the general formula (III) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (III), which has the formula (IIId):

In one embodiment of general formula (IIId), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In one embodiment of general formula (IIId), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

In one embodiment, the present disclosure relates to a compound offormula (IV) or a pharmaceutically acceptable salt thereof:

X₁, X₂ and X₃ are each independently selected from N or CR_(a);

Y is selected from N, O, S or CR_(a);

Z₁ and Z₂ are each independently selected from N or C, and Z₁ and Z₂ arenot N at the same time;

p, and q represent single bond or double bond, and there is one and onlyone double bond in p and q;

r, and s represent single bond or double bond, and there is one and onlyone double bond in r and s;

provided that when q and r are both single bond, Y is not CR_(a),

provided that when Z₁ is N, X₁, X₂, X₃ and Y are not CR_(a) at the sametime;

each R_(a) is independently selected from H, halogen, cyano, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₀R₁₁, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

C₁ and C₂ are each independently selected from CH or N;

R₁ and R₃ are each independently absent or are H, halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl, wherein the C₁₋₆ alkyl isoptionally substituted by one, two or three groups selected from C₁₋₃alkyl, hydroxy or C₁₋₃ alkoxy;

R₂ is absent or is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl; wherein the said C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl and 4- to 7-membered heterocyclyl are each optionallysubstituted by one, two or three R₁₄;

wherein R₁ and R₂, or R₂ and R₃ can be combined to form a C₅₋₇cycloalkyl ring or 5- to 7-membered heterocyclyl ring, and wherein thesaid C₅₋₇ cycloalkyl ring and 5- to 7-membered heterocyclyl ring areeach independently substituted by one, two or three R₁₄;

R₄ is H, halogen, hydroxy, amino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl;

L is selected from —C(O)NR₉—, —NR₉C(O)—, —NR₉C(O)NR₉— or

ring B is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl;

R₅ is absent or is H, halogen, cyano, hydroxy, amino, C₁₋₆ alkyl or C₁₋₆alkoxy;

R₆ and R₇ are absent or are H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl, wherein the said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl areoptionally substituted by one, two or three R₁₄;

R₈ is absent or is H or 5- to 7-membered heteroaryl, wherein the said 5-to 7-membered heteroaryl is optionally substituted by one, two or threeR₁₅;

wherein R₅ and R₆, R₆ and R₇, or R₇ and R₈ can be combined to form aC₅₋₇ cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ arylring or 5- to 12-membered heteroaryl ring, and wherein the said C₅₋₇cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ aryl ring and5- to 12-membered heteroaryl ring are each independently substituted byone, two or three R₁₄;

R₉, R₁₀ and R₁₁ are each independently selected from H or C₁₋₃ alkyl;

R₁₂ and R₁₃ are each independently H or C₁₋₆ alkyl; or Ru and R₁₃together with the nitrogen to which they attached form a 4- to7-membered heterocyclyl ring, wherein the formed 4- to 7-memberedheterocyclyl ring is optionally substituted by one, two or three R₁₅;

each R₁₄ is independently selected from halogen, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, —NR₁₆R₁₇, —C(O)NR₁₈R₁₉, C₃₋₇ cycloalkyl or 3- to7-membered heterocyclyl, wherein the said C₃₋₇ cycloalkyl and 3- to7-membered heterocyclyl are optionally substituted by one, two or threeR₁₅;

each R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl,C₁₋₃ alkoxy or —NR₂₀R₂₁;

R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ and R₂₁ are each independently H or C₁₋₃ alkyl.

In one embodiment of general formula (IV), X₁, X₂ and X₃ are eachindependently selected from N or CH, Y is selected from N or CH, Z₁ andZ₂ are each independently N or C, and at least two of X₁, X₂, X₃, Y, Z₁and Z₂ are N.

In one alternative embodiment,

has the following structure

wherein X₁, X₂, X₃ and Y are each independently selected from N or CH,and X₁, X₂, X₃ and Y are not all CH; in another alternative embodiment,

is selected from the group with the following structures:

In another alternative embodiment,

has the following structure

wherein X₁, X₂, X₃ and Y are each independently selected from N or CH.

In another alternative embodiment,

has the following structure

wherein X₁, X₂, X₃ and Y are each independently selected from N or CH.

In one embodiment of general formula (IV), R₁ and R₃ are eachindependently selected from H, halogen, —NH₂, C₁₋₆ haloalkyl or C₁₋₆alkyl, and wherein the said C₁₋₆ alkyl is optionally substituted by onehydroxy. In one alternative embodiment, R₁ and R₃ are each independentlyselected from H, F, —NH₂ or —CF₃. In another alternative embodiment, R₁and R₃ are C₁₋₃ alkyl optionally substituted by hydroxy.

In one embodiment of general formula (IV), R₂ is selected from C₁₋₆alkyl, C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl, wherein thesaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl areeach optionally substituted by one or two R₁₄. In one alternativeembodiment, R₂ is selected from methyl, ethyl, isopropyl, —(CH₂)₂OCH₃,—(CH₂)₃OCH₃, —(CH₂)₂N(CH₃)₂, —(CH₂)₃N(CH₃)₂, piperidinyl orN-methylpiperidinyl.

In one embodiment of general formula (IV), R₁ and R₂, or R₂ and R₃ canbe combined to form a 5- to 6-membered heterocyclyl ring, and whereinthe said 5- to 6-membered heterocyclyl ring is each independentlysubstituted by one, two or three R₁₄. In one alternative embodiment, R₁and R₂, or R₂ and R₃ can be combined to form a piperidine ring or apiperazine ring, wherein the said piperidine ring or piperazine ring isoptionally substituted by one or two R₁₄.

In one embodiment of general formula (IV), R₄ is selected from H, F ormethyl. In one alternative embodiment, R₄ is methyl.

In one embodiment of general formula (IV), L is selected from —C(O)NH—,—NHC(O)—, —NHC(O)NH— or

In one alternative embodiment, L is —C(O)NH—; in another alternativeembodiment, L is —NHC(O)—.

In one embodiment of general formula (IV), ring B is selected from C₆₋₁₀aryl ring or 5- to 12-membered heteroaryl ring. In one alternativeembodiment, ring B is selected from benzene, pyridine, isoxazole,quinoline or benzothiazole.

One embodiment of the general formula (IV) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound ofthe formula (IV), which has the formula (IVa):

wherein,

U₁ is selected from CH or N;

U₂ is selected from CR₈ or N;

U₃ is selected from CR₇ or N.

In one embodiment of general formula (IVa), R₅ is selected from H, F, Clor methyl.

In one embodiment of general formula (IVa), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In one embodiment of general formula (IVa), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl, orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

In one embodiment of general formula (IVa), R₈ is selected from H,imidazolyl substituted with a C₁₋₃ alkyl.

One embodiment of the general formula (IV) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (IV), which has the formula (IVb):

In one embodiment of general formula (IVb), R₅ is selected from H, F, Clor methyl.

In one embodiment of general formula (IVb), R₆ is selected from H, F,methoxy, trifluoromethyl or C₁₋₆ alkyl optionally substituted by oneR₁₄. In one alternative embodiment, R₆ is tert-butyl. In anotheralternative embodiment, R₆ is 2-trifluoromethylprop-2-yl.

One embodiment of the general formula (IV) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound ofthe formula (IV), which has the formula (IVc):

In one embodiment of general formula (IVc), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In one embodiment of general formula (IVc), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

One embodiment of the general formula (IV) relates to a compound or apharmaceutically acceptable salt of any embodiment of the compound offormula (IV), which has the formula (IVd):

In one embodiment of general formula (IVd), R₆ is selected from H, F,methoxy or trifluoromethyl. In one alternative embodiment, R₆ istrifluoromethyl.

In one embodiment of general formula (IVd), R₇ is selected from H,halogen, trifluoromethyl, C₁₋₆ alkoxy, 5- to 6-membered heterocyclyl orC₁₋₃ alkyl optionally substituted by one or two R₁₄. In one alternativeembodiment, R₇ is selected from H, C₁ or trifluoromethyl; in anotheralternative embodiment, R₇ is methoxy; in another alternativeembodiment, R₇ is morpholinyl.

In another alternative embodiment, R₇ has the following structure:

wherein,

C₁ is selected from CR₁₄ or N;

C₂ is selected from C(R₁₄)₂ or NR₁₄;

m and n are each independently selected from 0, 1, 2 or 3.

In another alternative embodiment, R₇ is selected from the followinggroups:

In another embodiment, the compound of the present disclosure isselected from the following compounds:

The compounds of the present disclosure may include one or moreasymmetric centers, and thus may exist in a variety of stereoisomericforms, for example, enantiomers and/or diastereomers. For example, thecompounds of the present disclosure may be in the form of an individualenantiomer, diastereomer or geometric isomer (e.g., cis- andtrans-isomers), or may be in the form of a mixture of stereoisomers,including racemic mixture and a mixture enriched in one or morestereoisomers. The isomers can be separated from the mixture by themethods known to those skilled in the art, including chiral highpressure liquid chromatography (IIPLC) and the formation andcrystallization of chiral salts; or preferred isomers can be prepared byasymmetric synthesis.

It will be understood by those skilled in the art that the organiccompounds can form complexes with solvents in which they are reacted orfrom which they are precipitated or crystallized. These complexes areknown as “solvates.” Where the solvent is water, the complex is known as“hydrate.” The present disclosure encompasses all solvates of thecompounds of the present disclosure.

The term “solvate” refers to forms of a compound or a salt thereof,which are associated with a solvent, usually by a solvolysis reaction.This physical association may include hydrogen bonding. Conventionalsolvents include water, methanol, ethanol, acetic acid, DMSO, THF,diethyl ether, etc. The compounds described herein can be prepared, forexample, in crystalline form, and can be solvated. Suitable solvatesinclude pharmaceutically acceptable solvates and further include bothstoichiometric solvates and non-stoichiometric solvates. In some cases,the solvates will be capable of isolation, for example, when one or moresolvent molecules are incorporated into the crystal lattice of acrystalline solid. “Solvate” includes both solution-phase and isolatablesolvates. Representative solvates include hydrates, ethanolates andmethanolates.

The term “hydrate” refers to a compound that is associated with water.Generally, the number of water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, hydrates of a compound can be represented,for example, by a general formula R·x H₂O, wherein R is the compound,and x is a number greater than 0. Given compounds can form more than onetype of hydrates, including, for example, monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, for example,hemihydrates (R·0.5 H₂O)) and polyhydrates (x is a number greater than1, for example, dihydrates (R·2 H₂O) and hexahydrates (R·6 H₂O)).

Compounds of the present disclosure may be in an amorphous or acrystalline form (polymorph). Furthermore, the compounds of the presentdisclosure may exist in one or more crystalline forms. Therefore, thepresent disclosure includes all amorphous or crystalline forms of thecompounds of the present disclosure within its scope. The term“polymorph” refers to a crystalline form of a compound (or a salt,hydrate or solvate thereof) in a particular crystal packing arrangement.All polymorphs have the same elemental composition. Differentcrystalline forms generally have different X-ray diffraction patterns,infrared spectra, melting points, density, hardness, crystal shapes,optical and electrical properties, stability, and solubility.Recrystallization solvents, rate of crystallization, storagetemperatures, and other factors may cause one crystalline form todominate. Various polymorphs of a compound can be prepared bycrystallization under different conditions.

The present disclosure also comprises compounds that are labeled withisotopes, which are equivalent to those described in formula (I), butone or more atoms are replaced by atoms having an atom mass or massnumber that are different from that of atoms that are common in nature.Examples of isotopes which may be introduced into the compounds of thedisclosure include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹¹C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Compoundsof the present disclosure that comprise the above isotopes and/or otherisotopes of other atoms, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or prodrugs all are within the scopeof the present disclosure. Certain isotope-labeled compounds of thepresent disclosure, such as those incorporating radioactive isotopes(e.g., ³H and ¹⁴C), can be used for the measurement of the distributionof drug and/or substrate in tissue. Tritium, which is ³H and carbon-14,which is ¹⁴C isotope, are particularly preferred, because they are easyto prepare and detect. Furthermore, replaced by heavier isotopes, suchas deuterium, which is ²H, may provide therapeutic benefits due to thehigher metabolic stability, such as prolonging the half-life in vivo ordecreasing the dosage requirements, and thus may be preferred in somecases. Isotope-labeled compounds of formula (I) of the presentdisclosure and prodrugs thereof can be prepared generally by usingreadily available isotope-labeled reagents to replacenon-isotope-labeled reagents in the following schemes and/or theprocedures disclosed in the examples and preparation examples.

In addition, prodrugs are also included within the context of thepresent disclosure. The term “prodrug” as used herein refers to acompound that is converted in vivo into an active form that has medicaleffects by, for example, hydrolysis in blood. Pharmaceuticallyacceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugsas Novel Delivery Systems, A.C.S. Symposium Series, Vol. 14, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S.Ramon and H. Barbra “Improved oral drug delivery: solubility limitationsovercome by the use of prodrugs”, Advanced Drug Delivery Reviews (1996)19(2) 115-130, each of which are incorporated herein by reference.

The prodrugs are any covalently bonded compounds of the presentdisclosure, which release the parent compound in vivo when the prodrugis administered to a patient. Prodrugs are typically prepared bymodifying functional groups in such a way that the modifications can becleaved either by routine manipulation or decompose in vivo to yield theparent compound. Prodrugs include, for example, compounds of the presentdisclosure wherein the hydroxy, amino or sulfhydryl groups are bonded toany group that, when administered to a patient, cleaves to form thehydroxy, amino or sulfhydryl groups. Thus, representative examples ofprodrugs include (but are not limited to) the acetate/acetamide,formate/formamide and benzoate/benzamide derivatives of the hydroxy,amino or sulfhydryl functional groups of the compounds of formula (I).Furthermore, in the case of carboxylic acid (—COOH), esters such asmethyl esters and ethyl esters, etc. can be employed. The ester itselfmay be active in their own and/or hydrolyzable under in vivo conditionsin the human body. Suitable pharmaceutically acceptable in vivohydrolysable ester groups include those groups that can readily breakdown in the human body to release the parent acids or salts thereof.

Pharmaceutical Compositions, Formulations and Kits

In another aspect, the disclosure provides a pharmaceutical compositioncomprising a compound of the present disclosure (also referred to as the“active ingredient”) and a pharmaceutically acceptable excipient. Incertain embodiments, the pharmaceutical composition comprises aneffective amount of the active ingredient. In certain embodiments, thepharmaceutical composition comprises a therapeutically effective amountof the active ingredient. In certain embodiments, the pharmaceuticalcomposition comprises a prophylactically effective amount of the activeingredient.

A pharmaceutically acceptable excipient for use in the presentdisclosure refers to a non-toxic carrier, adjuvant or vehicle which doesnot destroy the pharmacological activity of the compound formulatedtogether. Pharmaceutically acceptable carriers, adjuvants, or vehiclesthat may be used in the compositions of the present disclosure include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins (e.g., human serum albumin), buffer substances(such as phosphate), glycine, sorbic acid, potassium sorbate, a mixtureof partial glycerides of saturated plant fatty acids, water, salt orelectrolyte (such as protamine sulfate), disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel,magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials,polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax,polyethylene-polyoxypropylene block polymers, polyethylene glycol andlanolin.

The present disclosure also includes kits (e.g., pharmaceutical packs).Kits provided may include a compound disclosed herein, other therapeuticagents, and a first and a second containers (e.g., vials, ampoules,bottles, syringes, and/or dispersible packages or other materials)containing the compound disclosed herein or other therapeutic agents. Insome embodiments, kits provided can also optionally include a thirdcontainer containing a pharmaceutically acceptable excipient fordiluting or suspending the compound disclosed herein and/or othertherapeutic agent. In some embodiments, the compound disclosed hereinprovided in the first container and the other therapeutic agentsprovided in the second container is combined to form a unit dosage form.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisdisclosure. The present disclosure, however, is not limited to thefollowing pharmaceutical compositions.

Exemplary Formulation 1—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 0.3-30 mg tablets(0.1-10 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 2—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 30-90 mg tablets (10-30mg of active compound per tablet) in a tablet press.

Exemplary Formulation 3—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 90-150 mg tablets(30-50 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 4—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 150-240 mg tablets(50-80 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 5—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 240-270 mg tablets(80-90 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 6—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 270-450 mg tablets(90-150 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 7—Tablets: A compound of the present disclosuremay be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 450-900 mg tablets(150-300 mg of active compound) in a tablet press.

Exemplary Formulation 8—Capsules: A compound of the present disclosuremay be admixed as a dry powder with a starch diluent in an approximate1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg ofactive compound per capsule).

Exemplary Formulation 9—Liquid: A compound of the present disclosure(125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) andthe resultant mixture may be blended, passed through a No. 10 mesh U.S.sieve, and then mixed with a previously made solution ofmicrocrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) in water. Sodium benzoate (10 mg), flavor, and color are dilutedwith water and added with stirring. Sufficient water may then be addedto produce a total volume of 5 mL.

Exemplary Formulation 10—Injection: A compound of the present disclosuremay be dissolved or suspended in a buffered sterile saline injectableaqueous medium to a concentration of approximately 5 mg/mL.

Administration

The pharmaceutical composition provided by the present disclosure may beadministered by a variety of routes including, but not limited to, oraladministration, parenteral administration, inhalation administration,topical administration, rectal administration, nasal administration,oral administration, vaginal administration, administration by implantor other means of administration. For example, parenteral administrationas used herein includes subcutaneous administration, intradermaladministration, intravenous administration, intramuscularadministration, intra-articular administration, intraarterialadministration, intrasynovial administration, intrasternaladministration, intracerebroventricular administration, intralesionaladministration, and intracranial injection or infusion techniques.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

When used to prevent the disorder disclosed herein, the compoundsprovided herein will be administered to a subject at risk for developingthe condition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

The pharmaceutical compositions provided herein can also be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a compound or pharmaceutical composition thereof overan extended period of time, e.g., for example, over 3 months, 6 months,1 year, 2 years, 3 years, 5 years, etc., or may be continuedindefinitely, for example, for the rest of the subject's life. Incertain embodiments, the chronic administration is intended to provide aconstant level of the compound in the blood, e.g., within thetherapeutic window over the extended period of time.

The pharmaceutical compositions of the present disclosure may be furtherdelivered using a variety of dosing methods. For example, in certainembodiments, the pharmaceutical composition may be given as a bolus,e.g., in order to raise the concentration of the compound in the bloodto an effective level rapidly. The placement of the bolus dose dependson the desired systemic levels of the active ingredient throughout thebody, e.g., an intramuscular or subcutaneous bolus dose allows a slowrelease of the active ingredient, while a bolus delivered directly tothe veins (e.g., through an IV drip) allows a much faster delivery whichquickly raises the concentration of the active ingredient in the bloodto an effective level. In other embodiments, the pharmaceuticalcomposition may be administered as a continuous infusion, e.g., by IVdrip, to provide maintenance of a steady-state concentration of theactive ingredient in the subject's body. Furthermore, in still yet otherembodiments, the pharmaceutical composition may be administered as firstas a bolus dose, followed by continuous infusion.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or alternativelyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or excipients and processing aids helpful for forming thedesired dosing form.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.01 to about 20 mg/kg of thecompound provided herein, with preferred doses each providing from about0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses, generally in anamount ranging from about 0.01 to about 20% by weight, alternativelyfrom about 0.1 to about 20% by weight, alternatively from about 0.1 toabout 10% by weight, and yet alternatively from about 0.5 to about 15%by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 2 g/dayfor a 40 to 80 kg human patient.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavours and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavouring agentsuch as peppermint, methyl salicylate, or orange flavouring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable excipients knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s). When formulated as anointment, the active ingredients will typically be combined with eithera paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with, for example anoil-in-water cream base. Such transdermal formulations are well-known inthe art and generally include additional ingredients to enhance thedermal penetration of stability of the active ingredients orFormulation. All such known transdermal formulations and ingredients areincluded within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration may be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compounds of the present disclosure can also be administered insustained release forms or from sustained release drug delivery systems.A description of representative sustained release materials may be foundin Remington's Pharmaceutical Sciences.

The present disclosure also relates to the pharmaceutically acceptableformulations of a compound of the present disclosure. In one embodiment,the formulation comprises water. In another embodiment, the formulationcomprises a cyclodextrin derivative. The most common cyclodextrins areα-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucoseunits, respectively, optionally comprising one or more substituents onthe linked sugar moieties, which include, but are not limited to,methylated, hydroxyalkylated, acylated, and sulfoalkylethersubstitution. In certain embodiments, the cyclodextrin is a sulfoalkylether β-cyclodextrin, e.g., for example, sulfobutyl etherβ-cyclodextrin, also known as Captisol. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the formulation compriseshexapropyl-β-cyclodextrin (e.g., 10-50% in water).

Treatment

The present disclosure provides compounds with biological propertiesthat enable these compounds to treat or ameliorate diseases of concernthat may involve kinases, the symptoms of these diseases, or the effectsof other physiological events mediated by kinases. For example, thecompounds of the present disclosure show inhibition of tyrosine kinaseactivity of Ret (Reaaranged during transfection),ABL1(E255K)-phosphorylated, ABL1(F317I)-nonphosphorylated,ABL1(F317I)-phosphorylated, ABL1(F317L)-nonphosphorylated,ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated,ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated,ABL1(Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated,ABL1(T315I)-nonphosphorylated, ABL1 (T315I)-phosphorylated,ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated,ABL2, ALK(L1196M), AMPK-alpha1, AMPK-alpha2, ANKK1, AURKB, AURKC, AXL,BLK, BMX, BRAF, BRAF(V600E), BRK, BTK, CAMK1, CAMKK1, CAMKK2, CDC2L1,CDC2L2, CDC2L5, CDK11, CDK2, CDK5, CDK7, CDK8, CDKL1, CDKL2, CDKL3,CHEK2, CIT, CLK1, CLK4, CSF1R, CSK, CTK, DDR1, DDR2, DLK, EGFR,EGFR(E746-A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P),EGFR(L747-S752del, P753S), EGFR(L747-T751del, Sins), EGFR(L858R),EGFR(L858R,T790M), EGFR(L861Q), EGFR(S752-1759del), EGFR(T790M), EPHA1,EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB4,EPHB6, ERBB2, ERBB4, ERK8, FAK, FER, FES, FGFR1, FGFR2, FGFR3,FGFR3(G697C), FGFR4, FGR, FLT1, FLT3, FLT3(D835H), FLT3(D835V),FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q),FLT3(N841I), FLT3(R834Q), FLT4, FRK, FYN, GAK, GCN2(Kin.Dom.2, S808G),HCK, HIPK4, HPK1, IKK-alpha, IKK-beta, IRAK1, IRAK4, ITK,JAK1(JH1domain-catalytic), JAK2(JH1domain-catalytic),JAK3(JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT(A829P),KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I),KIT(V559D,V654A), LCK, LIMK1, LIMK2, LOK, LRRK2, LRRK2(G2019S), LTK,LYN, MAK, MAP3K2, MAP3K3, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MEK5, MELK,MERTK, MET, MET(M1250T), MINK, MKNK2, MLK1, MLK2, MLK3, MST1, MST1R,MST2, MUSK, MYLK2, MYO3A, MYO3B, NDR2, NEK1, NEK11, NEK4, NEK5, NEK9,NLK, p38-alpha, p38-beta, p38-delta, p38-gamma, PCTK2, PDGFRA, PDGFRB,PFCDPK1(P. falciparum), PFTAIRE2, PFTK1, PKAC-alpha, PKAC-beta, PYK2,RAF1, RET, RET(M918T), RET(V804L), RET(V804M), RIPK1, RIPK2, RIPK4,ROCK2, RPS6KA4(Kin.Dom.1-N-terminal), RSK2(Kin.Dom.1-N-terminal),RSK3(Kin.DoN-terminal), S6K1, SIK, SLK, SRC, SRMS, SRPK1, STK33, STK35,STK36, SYK, TAK1, TAOK2, TAOK3, TEC, TESK1, TGFBR2, TIE1, TIE2, TNIK,TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TTK, TXK,TYK2(JH1domain-catalytic), TYRO3, ULK3, VEGFR2, YES, YSK4, ZAK, ZAP70 orFGFR(Fibroblast growth factor receptor), as well as other tyrosinekinases believed to regulate the growth, development and/or metastasisof cancer. Many compounds of the present disclosure have been found tohave potent in vitro activity against cancer cell lines, including K562leukemia cells.

Therefore these compounds are of concern for the treatment of cancer,the cancers include primary and metastatic cancers, including solidtumors and lymphomas and leukemias (including CML, AML, ALL, etc.), andalso include treatment for others (including treatment of resistantcancers involving the administration of kinase inhibitors, such asGleevec, Tarceva or Iressa).

These cancers include breast cancer, cervical cancer, colorectal cancer,lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, headand neck cancer, gastrointestinal stromal cancer, and the followingdiseases, such as melanoma, multiple myeloma, non-Hodgkin's lymphoma,gastric cancer, kidney cancer and leukemia (such as myeloid,lymphocytic, myelocytic and lymphoblastic leukemia), include diseasesthat are resistant to one or more other treatments (including Gleevec,Tarceva or Iressa).

Resistance to multiple anticancer drugs may be caused by mutations incancer mediators or effectors (e.g., mutations in kinases such as Src orAbl), which are related to the drug-binding properties,phosphate-binding properties, protein-binding properties, andself-regulation or related to other properties of patients. For example,in the case of BCR-ABL, resistance to Gleevec has been mapped to avariety of BCR/Abl mutations, which are related to various functionalconsequences, including steric hindrance caused by the occupation of theactive site of the kinase by the drug, the change in the variability ofthe phosphate-binding loop (P-loop), the effect on the structure of theactivation loop (A-loop) surrounding the active site, etc.

The effective amount of the compound of the present disclosure isusually at an average daily dose of 0.01 mg to 50 mg compound/kg patientbody weight, preferably 0.1 mg to 25 mg compound/kg patient body weight,in single or multiple dosages. Generally, the compound of the presentdisclosure can be administered to a patient in need of such treatment ata daily dose ranging from about 1 mg to about 3500 mg per patient,preferably 10 mg to 1000 mg. For example, the daily dose per patient canbe 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350,400, 500, 600, 700, 800, 900 or 1000 mg. The compound of the presentdisclosure can be administered once or multiple times daily, weekly (orat intervals of several days) or on an intermittent schedule. Forexample, the compound can be administered one or more times per day on aweekly basis (e.g. every Monday), timelessly or for several weeks, forexample 4-10 weeks. Alternatively, it may be administered daily forseveral days (e.g., 2-10 days), and then a drug holiday for few days(e.g., 1-30 days), repeat the cycle arbitrarily or in a given number oftimes, such as 4-10 times. For example, the compound of the presentdisclosure can be administered daily for 5 days, and then a drug holidayfor 9 days, and then administered daily for 5 days, then a drug holidayfor 9 days, and so on, repeating the cycle arbitrarily or repeating 4-10times in total.

Combination Therapy

The compounds of the present disclosure, the salts and solvates thereof,and physiologically functional derivatives thereof can be used alone orin combination with other therapeutic agents for the treatment ofvarious protein kinase-mediated diseases and conditions.

The combination therapy according to the present disclosure thereforeincludes the administration of at least one compound of formula (I) or apharmaceutically acceptable salt or solvate or physiologicallyfunctional derivative thereof and the use of at least one otherpharmaceutically active agent. One or more compounds of formula (I) andone or more other pharmaceutically active agents can be administeredtogether or separately, and can be administered simultaneously orsequentially in any order when administered separately. The amount andrelative timing of administration of one or more compounds of formula(I) and one or more other pharmaceutically active agents will beselected to achieve the desired combined therapeutic effect.

For the treatment of cancer, a compound of formula (I) may be combinedwith one or more of anticancer agents. Examples of such agents can befound in Cancer Principles and Practice of Oncology by V. T. Devita andS. Hellman (editors), 6^(th) edition (Feb. 15, 2001), LippincottWilliams & Wilkins Publishers. A person of ordinary skill in the artwould be able to discern which combinations of agents would be usefulbased on the particular characteristics of the drugs and the cancerinvolved. Such anti-cancer agents include, but are not limited to, thefollowing: (1) estrogen receptor modulator such as diethylstibestral,tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene,fluoxymestero, and SH646; (2) other hormonal agents including aromataseinhibitors (e.g., aminoglutethimide, tetrazole anastrozole, letrozoleand exemestane), luteinizing hormone release hormone (LHRH) analogues,ketoconazole, goserelin acetate, leuprolide, megestrol acetate andmifepristone; (3) androgen receptor modulator such as finasteride andother 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate; (4) retinoid receptor modulator suchas bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide; (5) antiproliferativeagent such as antisense RNA and DNA oligonucleotides such as G3139,ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such asenocitabine, carmofur, tegafur, pentostatin, doxifluridine,trimetrexate, fludarabine, capecitabine, galocitabine, cytarabineocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid,emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelarabine,2-deoxy-2-methylidenecytidine, 2-fluoromethylene-2′-deoxycytidine,N6-[4-deoxy-4[N2-[2(E),4(E)-tetradeca-dienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine, aplidine,ecteinascidin, troxacitabine, aminopterin, 5-fluorouracil, floxuridine,methotrexate, folinic acid, hydroxyurea, thioguanine (6-TG),mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate,cladribine (2-CDA), asparaginase, gemcitabine, alanosine, swainsonine,lometrexol, dexrazoxane, methioninase, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone; (6) prenyl-proteintransferase inhibitor including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-H (GGPTase-II, also called RabGGPTase); (7) HMG-CoA reductase inhibitor such as lovastatin,simvastatin, pravastatin, atorvastatin, fluvastatin and rosuvastatin;(8) angiogenesis inhibitor such as inhibitors of the tyrosine kinasereceptors Flt-1 (VEGFR1) and Flk-1/DR (VEGFR2), inhibitors ofepidermal-derived, fibroblast-derived, or platelet derived growthfactors, MMP (matrix metalloprotease) inhibitors, integrin blockers,interferon-α, interleukin-12, erythropoietin (epoietin-α),granulocyte-CSF (filgrastin), granulocyte, macrophage-CSF(sargramostim), pentosan polysulfate, cyclooxygenase inhibitors,steroidal anti-inflammatories, carboxyamidotriazole, combretastatin A-4,squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide,angiostatin, troponin-1, angiotensin II antagonists, heparin,carboxypeptidase U inhibitors, and antibodies against the followingsubjects: VEGF, endostatin, ukrain, ranpirnase, IM862, acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentaose phosphate, and3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416); (9) PPAR-γagonists, PPAR-6 agonists, thiazolidinediones (such as DRF2725, CS-011,troglitazone, rosiglitazone, and pioglitazone), fenofibrate,gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555,GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570,PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluotomethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid (disclosed in U.S. Ser. No. 09/782,856), and(2R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylicacid (disclosed in U.S. Ser. No. 60/235,708 and 60/244,697); (9)inhibitor of inherent multidrug resistance including inhibitors ofp-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922,VX853 and PSC833 (valspodar); (10) inhibitor of cell proliferation andsurvival signaling such as inhibitors of EGFR (for example gefitiniberlotinib, icotinib and osimertinib (AZD9291)), inhibitors of ERB-2 (forexample trastuzumab), inhibitors of IGF1R such as MK-0646 (dalotuzumab),inhibitors of CD20 (rituximab), inhibitors of cytokine receptors,inhibitors of MET, inhibitors of PI3K family kinase (for exampleLY294002), serine/threonine kinases (including but not limited toinhibitors of Akt such as described in (WO 03/086404, WO 03/086403, WO03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO02/083138), inhibitors of Raf kinase (for example BAY-43-9006),inhibitors of MEK (for example CI-1040 and PD-098059) and inhibitors ofmTOR (for example Wyeth CCI-779 and Ariad AP23573); (11) abisphosphonate such as etidronate, pamidronate, alendronate,risedronate, zoledronate, ibandronate, incadronate or cimadronate,clodronate, EB-1053, minodronate, neridronate, piridronate andtiludronate; (12) γ-secretase inhibitors, (13) agents that interferewith receptor tyrosine kinases (RTKs) including inhibitors of c-Kit,Eph, PDGF, Flt3 and c-Met; (14) agent that interferes with a cell cyclecheckpoint including inhibitors of ATR, ATM, the Chk1 and Chk2 kinasesand cdk and cdc kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032;(15) BTK inhibitors such as PCI32765, AVL-292 and AVL-101; (16) PARPinhibitors including iniparib, olaparib, AG014699, ABT888 and MK4827;(16) ERK inhibitors; (17) mTOR inhibitors such as rapamycin,42-(dimethylphosphinate) rapamycin, temsirolimus, everolimus; (18)cytotoxic/cytostatic agents.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell mytosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, inhibitors of histonedeacetylase, inhibitors of kinases involved in mitotic progression,antimetabolites; biological response modifiers; hormonal/anti-hormonaltherapeutic agents, haematopoietic growth factors, monoclonal antibodytargeted therapeutic agents, topoisomerase inhibitors and proteasomeinhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef,cachectin, chlorambucil, cyclophosphamide, ifosfarnide, mechiorethamine,melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine,streptozocin, tasonermin, lonidamine, carboplatin, altretamine,dacarbazine, procarbazine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosilate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine,glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)] bis[diamine(chloro)platinum (II)] tetrachloride, diarizidinylspermine,arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,doxorubicin, daunorubicin, idarubicin, anthracenedione, bleomycin,mitomycin C, dactinomycin, plicatomycin, bisantrene, mitoxantrone,pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, kanamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin.

Examples of proteasome inhibitors include but are not limited tolactacystin and bortezomib.

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude vincristine, vinblastine, vindesine, vinzolidine, vinorelbine,vindesine sulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine,podophyllotoxins (e.g., etoposide (VP-16) and teniposide (VM-26)),paclitaxel, docetaxol, rhizoxin, dolastatin, mivobulin isethionate,auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin, lurtotecan,7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100,BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimemylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2-(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethyiamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

Examples of “histone deacetylase inhibitors” include, but are notlimited to, vorinostat, trichostatin A, oxamfiatin, PXD101, MG98,valproic acid and scriptaid.

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R₁. An example of an “aurora kinase inhibitor” isVX-680.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelarabine, 2-deoxy-2-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N6-[4-deoxy-4-[N2-[2,4-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine, aminopterin, 5-flurouracil,floxuridine, methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG),mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate,cladribine (2-CDA), asparaginase, gemcitabine, alanosine, swainsonine,lometrexol, dexrazoxane, methioninase, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Non-limiting examples of suitable agents used in cancer therapy that maybe combined with compounds of formula (I) include, but are not limitedto, abarelix; aldesleukin; alemtuzumab; alitretinoin; allopurinol;altretamine; amifostine; anastrozole; arsenic trioxide; asparaginase;azacitidine; bendamustine; bevacizumab; bexarotene; bleomycin;bortezomib; busulfan; calusterone; capecitabine; carboplatin;carmustine; cetuximab; chlorambucil; cisplatin; cladribine; clofarabine;cyclophosphamide; cytarabine; dacarbazine; dactinomycin, actinomycin D;dalteparin sodium; erythropoietin; dasatinib; daunorubicin; degarelix;denileukin diftitox; dexrazoxane; docetaxel; adriamycin; dromostanolonepropionate; eculizumab; Elliott's B Solution; eltrombopag; epirubicin;epoetin alfa; erlotinib; estramustine; etoposide phosphate; etoposide;everolimus; exemestane; filgrastim; floxuridine; fludarabine;fluorouracil; fulvestrant; iressa; tarceva; osimertinib; gemcitabine;gemtuzumab; goserelin acetate; histrelin acetate; hydroxyurea;ibritumomab tiuxetan; idarubicin; ifosfamide; imatinib mesylate;interferon alfa-2a; interferon alfa-2b; irinotecan; ixabepilone;lapatinib; lenalidomide; letrozole; leucovorin; leuprolide acetate;levamisole; lomustine; meclorethamine, chlormethine; megestrol acetate;melphalan, L-PAM; mercaptopurine; mesna; methotrexate; methoxsalen;mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate;nelarabine; nilotinib; Nofetumomab; ofatumumab; oprelvekin; oxaliplatin;paclitaxel; palifermin; pamidronate disodium; panitumumab; pazopanib;pegademase; pegaspargase; Pegfilgrastim; pemetrexed disodium;pentostatin; pipobroman; plerixafor; plicamycin, mithramycin; porfimersodium; pralatrexate; ibenzmethyzin; quinacrine; Rasburicase; raloxifenehydrochloride; Rituximab; romidepsin; romiplostim; sargramostim;sargramostim; satraplatin; sorafenib; streptozocin; sunitinib maleate;tamoxifen; temozolomide; temsirolimus; teniposide; testolactone;thioguanine; thiotepa; topotecan; toremifene; tositumomab; trastuzumab;tretinoin; uracil mustard; valrubicin; vinblastine; vincristine;vinorelbine; vorinostat; and zoledronic acid.

It is clear to those skilled in the art that, where appropriate, theother one or more therapeutic ingredients may be used in the form ofsalt, such as alkali metal salt or amine salt or acid addition, orprodrug, or ester such as lower alkyl ester, or solvate such as hydrateto optimize the activity and/or stability and/or physical properties(such as solubility) of the therapeutic ingredient. It is also clearthat, where appropriate, the therapeutic ingredients can be used inoptically pure form.

The above-mentioned combination can be conveniently used in the form ofa pharmaceutical composition, so a pharmaceutical composition comprisingthe above-mentioned combination and a pharmaceutically acceptablediluent or carrier represents another aspect of the present disclosure.These combinations are particularly useful for respiratory diseases andare conveniently suitable for inhalation or intranasal delivery.

The compounds of this combination can be administered sequentially orsimultaneously in the form of separate or combined pharmaceuticalcompositions. Preferably, each compound is administered simultaneouslyin the form of combined pharmaceutical composition. Those skilled in theart will readily understand the appropriate dosage of the knowntherapeutic agent.

EXAMPLES

The present disclosure will be further described below in combinationwith specific embodiments. It should be understood that these examplesare only used to illustrate the present disclosure and not to limit thescope of the present disclosure. The experimental methods withoutspecific conditions in the following examples generally follow theconventional conditions or the conditions recommended by themanufacturer. Unless otherwise stated, parts and percentages are partsby weight and weight percent.

Generally, in the preparation process, each reaction is carried out inan inert solvent at a temperature from room temperature to refluxtemperature (such as 0° C. to 100° C., alternatively 0° C. to 80° C.).The reaction time is usually 0.1-60 hours, alternatively 0.5-24 hours.

The abbreviations used in this article have the following meanings:

APCI Atmosphere Pressure Chemical Ionization IPA Isopropanol TEATriethylamine DIEA N,N-diisopropylethylamine DMF N,N-dimethyl formamideTBAF Tetrabutylammonium fluoride THF Tetrahydrofuran TsCl4-Toluenesulfonyl chloride DCM Dichloromethane NBS N-bromosuccinimide

Example 1 Preparation ofN-(4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)ethynyl)phenyl)-3-(trifluoromethyl)benzamide(Compound I-1)

The following route was used for the synthesis:

Step 1: Synthesis of Compound 8-chloroimidazo[1,2-a]pyrazine

3-chloropyrazin-2-amine (1.29 g, 10 mmol) and chloroacetaldehyde (40%aqueous solution, 9.8 g, 50 mmol) were added into 30 mL of IPA, whichwas heated to reflux overnight. The solvent was removed by rotaryevaporation, 30 mL water was added to dissolve the residue, andsaturated sodium bicarbonate solution was added to adjust pH=7, and thereaction solution was extracted with ethyl acetate (20 mL*3), theorganic phases were combined, washed with 20 mL saturated brine, driedover anhydrous sodium sulfate, concentrated, and separated by silica gelcolumn to afford 1.07 g of light yellow solid. Yield: 70%. LC-MS(APCI):m/z=154(M+1)⁺.

Step 2: Synthesis of Compound 3-bromo-8-chloroimidazo[1,2-a]pyrazine

8-chloroimidazo[1,2-a]pyrazine (1.07 g, 7 mmol) was dissolved in 15 mLglacial acetic acid, liquid bromine (1.12 g, 7 mmol) was slowly addeddropwise to the reaction under an ice bath. The ice bath was removedafter the completion of addition, and the reaction was stirred at roomtemperature overnight. TLC was used to monitor the completion of thereaction. 30 mL of saturated sodium sulfite solution was added, and thereaction solution was extracted with ethyl acetate (30 mL*3), theorganic phases were combined, washed with 20 mL of saturated brine,dried over anhydrous sodium sulfate, concentrated, and separated bysilica gel column to afford 1.33 g of light yellow solid. Yield: 82%.LC-MS(APCI): m/z=233(M+1)⁺.

Step 3: Synthesis of Compound3-bromo-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine

3-bromo-8-chloroimidazo[1,2-a]pyrazine (1.33 g, 5.7 mmol),1-methyl-1H-pyrazol-4-amine (0.66 g, 6.8 mmol) and triethylamine (1.15g, 11.4 mmol) were added to 15 mL of n-butanol, the reaction was heatedto 120° C. and reacted overnight. The solvent was removed by rotaryevaporation, 30 mL water was added to dissolve the residue, and thereaction solution was extracted with ethyl acetate (20 mL*3), theorganic phases were combined, washed with 20 mL of saturated brine,dried over anhydrous sodium sulfate, concentrated, and separated bysilica gel column to afford 1.25 g of light yellow solid. Yield: 75%.LC-MS(APCI): m/z=294(M+1)⁺.

Step 4: Synthesis of CompoundN-(1-methyl-1H-pyrazol-4-yl)-3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyrazin-8-amine

3-bromo-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (1.25g, 4.3 mmol), trimethylsilylacetylene (0.54 g, 5.5 mmol), Pd(PPh₃)₄(0.24 g, 0.21 mmol), CuI (51 mg, 0.33 mmol) and 1.4 mLN,N-diisopropylethylamine were added to 10 mL DMF, the atmosphere wasreplaced with nitrogen for 3 times, the reaction was heated to 90° C.,and reacted for 3 hours. After the completion of reaction, the reactionwas cooled to room temperature, added with 30 mL of water, and thereaction solution was extracted with ethyl acetate (20 mL*3), and theorganic phase was washed with 10 mL saturated brine, dried overanhydrous sodium sulfate, concentrated, and separated by silica gelcolumn to afford 0.8 g of light yellow solid. Yield: 60%. LC-MS (APCI):m/z=311(M+1)⁺.

Step 5: Synthesis of Compound3-ethynyl-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine

N-(1-methyl-1H-pyrazol-4-yl)-3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyrazin-8-amine(0.8 g, 2.58 mmol) was dissolved in 10 mL of tetrahydrofuran, andtetrabutylammonium fluoride (1.35 g, 5.16 mmol) was added, the reactionwas stirred at room temperature for 1 hour. The solvent was removed byrotary evaporation, 10 mL of water was added, and the reaction solutionwas extracted with ethyl acetate (10 mL*3), and the organic phase waswashed with 10 mL saturated brine, dried over anhydrous sodium sulfate,concentrated, and separated by silica gel column to afford 0.54 g oflight yellow solid. Yield: 88%. LC-MS(APCI): m/z=239(M+1)⁺.

Step 6: Synthesis of CompoundN-(4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)ethynyl)phenyl)-3-(trifluoromethyl)benzamide

N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide (125 mg, 0.31mmol),3-ethynyl-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (90mg, 0.38 mmol), Pd(PPh₃)₄ (11 mg, 0.01 mmol), CuI (4 mg, 0.02 mmol) and0.12 mL N,N-diisopropylethylamine were added to 5 mL of DMF, theatmosphere was replaced with nitrogen for 3 times, the reaction washeated to 90° C., and reacted for 3 hours. After the completion ofreaction, the reaction was cooled to room temperature, 20 mL of waterwas added, and the reaction solution was extracted with ethyl acetate(10 mL*3), and the organic phase was washed with 10 mL saturated brine,dried over anhydrous sodium sulfate, concentrated, and separated bysilica gel column to afford 100 mg of light yellow solid. Yield: 63%.LC-MS(APCI): m/z=516(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.54 (s, 1H),10.06 (s, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.28 (d, J=7.9 Hz, 1H), 8.19 (s,1H), 8.09 (d, J=2.3 Hz, 1H), 8.04 (s, 1H), 7.99 (d, J=7.8 Hz, 1H),7.88-7.78 (m, 2H), 7.75-7.70 (m, 2H), 7.62 (d, J=4.5 Hz, 1H), 7.38 (d,J=8.4 Hz, 1H), 3.84 (s, 3H), 2.52 (s, 3H).

Example 2 Preparation of4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)ethynyl)-N-(3-(trifluoromethyl)phenyl)benzamide(Compound I-2)

The title compound I-2 was prepared according to the synthetic methoddescribed in Example 1, and compound3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide was used toreplace N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide in step6. LC-MS(APCI): m/z=516(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ10.61 (s, 1H),10.06 (s, 1H), 8.30-8.25 (m, 2H), 8.19 (s, 1H), 8.09 (d, J=8.3 Hz, 1H),8.05 (s, 1H), 7.98-7.91 (m, 2H), 7.75 (s, 1H), 7.62 (dd, J=9.6, 6.3 Hz,2H), 7.57 (d, J=8.1 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 3.84 (s, 3H), 2.62(s, 3H).

Example 3 Preparation ofN-(4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)ethynyl)phenyl)-2-(trifluoromethyl)isonicotinamide(Compound I-3)

The title compound I-3 was prepared according to the synthetic methoddescribed in Example 1, and compoundN-(3-iodo-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide was used toreplace N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide in step6. LC-MS(APCI): m/z=517(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (s,1H), 10.06 (s, 1H), 9.01 (d, J=5.0 Hz, 1H), 8.39 (s, 1H), 8.24-8.17 (m,2H), 8.09 (d, J=2.2 Hz, 1H), 8.05 (s, 1H), 7.84 (d, J=4.5 Hz, 1H), 7.75(s, 1H), 7.71 (dd, J=8.3, 2.3 Hz, 1H), 7.62 (d, J=4.5 Hz, 1H), 7.41 (d,J=8.4 Hz, 1H), 3.84 (s, 3H), 2.52 (s, 3H).

Example 4 Preparation of3-(4-methyl-1H-imidazol-1-yl)-N-(4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)ethynyl)phenyl)-5-(trifluoromethyl)benzamide(Compound I-4)

The title compound I-4 was prepared according to the synthetic methoddescribed in Example 1, and compoundN-(3-iodo-4-methylphenyl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamidewas used to replaceN-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide in step 6.LC-MS(APCI): m/z=596(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H),10.06 (s, 1H), 8.30-8.25 (m, 2H), 8.19 (s, 1H), 8.09 (d, J=8.3 Hz, 1H),8.05 (s, 1H), 7.98-7.91 (m, 2H), 7.78 (s, 1H), 7.73 (s, 1H), 7.68 (s,1H), 7.62 (s, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 3.84(s, 3H), 2.54 (s, 3H), 2.18 (s, 3H).

Example 5 Preparation ofN-(4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)ethynyl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide(Compound I-5)

The title compound I-5 was prepared according to the synthetic methoddescribed in Example 1, and compoundN-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamidewas used to replaceN-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide in step 6.LC-MS(APCI): m/z=628(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.62 (s, 1H),9.42 (s, 1H), 8.25 (d, J=5.4 Hz, 2H), 8.21 (s, 1H), 8.13 (d, J=8.9 Hz,1H), 8.05 (s, 1H), 7.97-7.91 (m, 2H), 7.74 (d, J=8.5 Hz, 1H), 7.58 (s,1H), 7.53 (d, J=8.1 Hz, 1H), 6.42 (d, J=5.7 Hz, 1H), 3.85 (s, 3H), 3.60(s, 2H), 2.81 (s, 4H), 2.61 (s, 3H), 2.56 (s, 4H), 2.49 (s, 3H).

Example 6 Preparation of5-(tert-butyl)-N-(4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)ethynyl)phenyl)isoxazole-3-carboxamide(Compound I-6)

The title compound I-6 was prepared according to the synthetic methoddescribed in Example 1, and compound5-(tert-butyl)-N-(3-iodo-4-methylphenyl)isoxazole-3-carboxamide was usedto replace N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide instep 6. LC-MS(APCI): m/z=495(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.72(s, 1H), 10.05 (s, 1H), 8.18 (s, 1H), 8.09-8.01 (m, 2H), 7.83 (d, J=4.5Hz, 1H), 7.71 (d, J=14.9 Hz, 2H), 7.61 (d, J=4.5 Hz, 1H), 7.36 (d, J=8.3Hz, 1H), 6.69 (s, 1H), 3.83 (s, 3H), 2.49 (s, 3H), 1.36 (s, 9H).

Example 7 Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)ethynyl)phenyl)urea(Compound I-7)

The title compound I-7 was prepared according to the synthetic methoddescribed in Example 1, and compoundI-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-iodo-4-methylphenyl)urea wasused to replace N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamidein step 6. LC-MS(APCI): m/z=566(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ10.05(s, 1H), 9.23 (s, 1H), 8.92 (s, 1H), 8.18 (s, 1H), 8.13 (d, J=2.2 Hz,1H), 8.03 (s, 1H), 7.85-7.82 (m, 2H), 7.74 (s, 1H), 7.64-7.60 (m, 2H),7.37-7.27 (m, 2H), 3.84 (s, 3H), 2.47 (s, 3H).

Example 8 Preparation ofN-(3-((8-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)ethynyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide(Compound I-8)

The following route was used for the synthesis:

Step 1: Synthesis of Compound3-bromo-N-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine

3-bromo-8-chloroimidazo[1,2-a]pyrazine (1.33 g, 5.7 mmol),1-(2-methoxyethyl)-1H-pyrazole-4-amine (0.96 g, 6.8 mmol) were added to15 mL of n-butanol, the reaction was heated to 120° C. and reactedovernight. The solvent was removed by rotary evaporation, 30 mL waterwas added to dissolve the residue, and the reaction solution wasextracted with ethyl acetate (20 mL*3), the organic phases werecombined, washed with 20 mL of saturated brine, dried over anhydroussodium sulfate, concentrated, and separated by silica gel column toafford 1.45 g of light yellow solid. Yield: 76%. LC-MS(APCI):m/z=338(M+1)⁺.

Step 2: Synthesis of CompoundN-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyrazin-8-amine

3-bromo-N-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine(1.45 g, 4.3 mmol), trimethylsilylacetylene (0.54 g, 5.5 mmol),Pd(PPh₃)₄ (0.24 g, 0.21 mmol), CuI (51 mg, 0.33 mmol) and 1.4 mL ofN,N-diisopropylethylamine were added to 10 mL of DMF, the atmosphere wasreplaced with nitrogen for 3 times, the reaction was heated to 90° C.,and reacted for 3 hours. After the completion of reaction, the reactionwas cooled to room temperature, added with 30 mL of water, and thereaction solution was extracted with ethyl acetate (20 mL*3), and theorganic phase was washed with 10 mL saturated brine, dried overanhydrous sodium sulfate, concentrated, and separated by silica gelcolumn to afford 0.96 g of light yellow solid. Yield: 63%. LC-MS(APCI):m/z=355(M+1)⁺.

Step 3: Synthesis of Compound3-ethynyl-N-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine

N-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyrazin-8-amine(0.96 g, 2.71 mmol) was dissolved in 10 mL of tetrahydrofuran,tetrabutylammonium fluoride (1.42 g, 5.42 mmol) was added, the reactionwas stirred at room temperature for 1 hour. The solvent was removed byrotary evaporation, 10 mL of water was added, and the reaction solutionwas extracted with ethyl acetate (10 mL*3), and the organic phase waswashed with 10 mL saturated brine, dried over anhydrous sodium sulfate,concentrated, and separated by silica gel column to afford 0.66 g oflight yellow solid. Yield: 86%. LC-MS(APCI): m/z=283(M+1)⁺.

Step 4: Synthesis of CompoundN-(3-(((8-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)ethynyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide

N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide (125 mg, 0.31mmol),3-ethynyl-N-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine(110 mg, 0.4 mmol), Pd(PPh₃)₄ (11 mg, 0.01 mmol), CuI (4 mg, 0.02 mmol)and 0.12 mL N,N-diisopropylethylamine were added to 5 mL of DMF, theatmosphere was replaced with nitrogen for 3 times, the reaction washeated to 90° C., and reacted for 3 hours. After the completion ofreaction, the reaction was cooled to room temperature, 20 mL of waterwas added, and the reaction solution was extracted with ethyl acetate(10 mL*3), and the organic phase was washed with 10 mL saturated brine,dried over anhydrous sodium sulfate, concentrated, and separated bysilica gel column to afford 110 mg of light yellow solid. Yield: 64%.LC-MS(APCI): m/z=560(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H),10.06 (s, 1H), 8.34-8.26 (m, 2H), 8.22 (s, 1H), 8.07 (d, J=14.4 Hz, 2H),7.99 (d, J=7.6 Hz, 1H), 7.82 (dd, J=15.5, 6.8 Hz, 3H), 7.73 (d, J=8.1Hz, 1H), 7.63 (d, J=4.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 4.25 (t, J=5.3Hz, 2H), 3.68 (t, J=5.3 Hz, 2H), 3.24 (s, 3H), 2.51 (s, 3H).

Example 9 Preparation ofN-(3-((8-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)ethynyl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(Compound I-9)

The title compound I-9 was prepared according to the synthetic methoddescribed in Example 8, and compoundN-(3-iodo-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide was used toreplace N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide in step4. LC-MS(APCI): m/z=561(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (s,1H), 10.06 (s, 1H), 9.01 (d, J=5.0 Hz, 1H), 8.39 (d, J=1.4 Hz, 1H), 8.21(d, J=4.5 Hz, 2H), 8.09 (d, J=2.2 Hz, 1H), 8.05 (s, 1H), 7.84 (d, J=4.6Hz, 1H), 7.78 (s, 1H), 7.72 (dd, J=8.4, 2.3 Hz, 1H), 7.63 (d, J=4.6 Hz,1H), 7.41 (d, J=8.5 Hz, 1H), 4.25 (t, J=5.3 Hz, 2H), 3.68 (t, J=5.3 Hz,2H), 3.24 (s, 3H), 2.53 (s, 3H).

Example 10 Preparation of5-(tert-butyl)-N-(3-((8-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyrazin-3-yl)ethynyl)-4-methylphenyl)isoxazole-3-carboxamide(Compound I-10)

The title compound I-10 was prepared according to the synthetic methoddescribed in Example 8, and compound5-(tert-butyl)-N-(3-iodo-4-methylphenyl)isoxazole-3-carboxamide was usedto replace N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide instep 4. LC-MS(APCI): m/z=539(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.72(s, 1H), 10.05 (s, 1H), 8.21 (s, 1H), 8.10-8.02 (m, 2H), 7.83 (d, J=4.6Hz, 1H), 7.77 (s, 1H), 7.70 (dd, J=8.3, 2.3 Hz, 1H), 7.62 (d, J=4.6 Hz,1H), 7.36 (d, J=8.4 Hz, 1H), 6.69 (s, 1H), 4.24 (t, J=5.3 Hz, 2H), 3.67(t, J=5.3 Hz, 2H), 3.23 (s, 3H), 2.49 (s, 3H), 1.35 (s, 9H).

Example 11 Preparation ofN-(4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)-3-(trifluoromethyl)benzamide(Compound I-11)

The following route was used for the synthesis:

Step 1: Synthesis of Compound8-(benzyloxy)-6-chloroimidazo[1,2-b]pyridazine

Benzyl alcohol (1.2 g, 11 mmol) was dissolved in 20 mL oftetrahydrofuran, and sodium hydride (60%, dispersed in liquid paraffin,0.44 g, 11 mmol) was added under an ice bath, the reaction solution wasstirred at room temperature for half an hour.8-bromo-6-chloroimidazo[1,2-b]pyridazine (2.32 g, 10 mmol) was slowlyadded under an ice bath, the ice bath was removed and the reaction wasreacted overnight at room temperature. TLC was used to monitor thecompletion of the reaction. 30 mL water was added to dissolve theresidue, the reaction solution was extracted with ethyl acetate (20mL*3), the organic phases were combined, washed with 20 mL of saturatedbrine, dried over anhydrous sodium sulfate, concentrated, and separatedby silica gel column to afford 2.24 g of light yellow solid. Yield:86.5%, LC-MS(APCI): m/z=260(M+1)⁺.

Step 2: Synthesis of Compound imidazo[1,2-b]pyridazin-8-ol

8-(benzyloxy)-6-chloroimidazo[1,2-b]pyridazine (2.24 g, 8.6 mmol) wasdissolved in 20 mL of methanol, 200 mg 10% palladium on carbon wasadded, the atmosphere was replaced with hydrogen for 3 times, thereaction was stirred overnight at room temperature under hydrogenatmosphere of 1 atm. Palladium on carbon was filtered off after thecompletion of reaction, the filtrate was concentrated, dried to afford1.05 g of white solid. Yield: 90%. LC-MS(APCI): m/z=136(M+1)⁺.

Step 3: Synthesis of Compound imidazo[1,2-b]pyridazin-8-yl4-methylbenzenesulfonate

Imidazo[1,2-b]pyridazin-8-ol (1.05 g, 7.8 mmol) and triethylamine (1.58g, 15.6 mmol) were added to 20 mL of dichloromethane,4-methylbenzenesulfonyl chloride (1.8 g, 9.4 mmol) was added under anice bath, the reaction was reacted at room temperature for 2 hours. TLCwas used to monitor the completion of the reaction. The reactionsolution was washed with 20 mL of water and 10 mL of saturated brine,respectively, dried over anhydrous sodium sulfate, concentrated, andseparated by silica gel column to afford 2.06 g of white solid. Yield:92%. LC-MS(APCI): m/z=290(M+1)⁺.

Step 4: Synthesis of Compound 3-bromoimidazo[1,2-b]pyridazin-8-yl4-methylbenzenesulfonate

Imidazo[1,2-b]pyridazin-8-yl 4-methylbenzenesulfonate (2.06 g, 7.1 mmol)was dissolved in 20 mL of dichloromethane, NBS (1.34 g, 7.5 mmol) wasadded under an ice bath, the reaction was reacted at room temperaturefor 2 hours. TLC was used to monitor the completion of the reaction. Thereaction solution was washed with 20 mL of water, dried over anhydroussodium sulfate, concentrated, and separated by silica gel column toafford 2.1 g of light yellow solid. Yield: 80%. LC-MS(APCI):m/z=369(M+1)⁺.

Step 5: Synthesis of Compound3-bromo-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-amine

3-bromoimidazo[1,2-b]pyridazin-8-yl 4-methylbenzenesulfonate (2.1 g, 5.7mmol), 1-methyl-1H-pyrazole-4-amine (0.66 g, 6.8 mmol) and triethylamine(1.15 g, 11.4 mmol) were added to 15 mL of n-butanol, the reactionsolution was heated to 120° C. and reacted overnight. The solvent wasremoved by rotary evaporation, 30 mL of water was added to dissolve theresidue, and the reaction solution was extracted with ethyl acetate (20mL*3), the organic phases were combined, washed with 20 mL of saturatedbrine, dried over anhydrous sodium sulfate, concentrated, and separatedby silica gel column to afford 1.25 g of light yellow solid. Yield: 75%.LC-MS (APCI): m/z=294(M+1)⁺.

Step 6: Synthesis of CompoundN-(1-methyl-1H-pyrazol-4-yl)-3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-8-amine

3-bromo-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-amine(1.26 g, 4.3 mmol), trimethylsilylacetylene (0.54 g, 5.5 mmol),Pd(PPh₃)₄ (0.24 g, 0.21 mmol), CuI (51 mg, 0.33 mmol) and 1.4 mLN,N-diisopropylethylamine were added to 10 mL DMF, the atmosphere wasreplaced with nitrogen for 3 times, the reaction was heated to 90° C.,and reacted for 3 hours. After the completion of reaction, the reactionwas cooled to room temperature, added with 30 mL of water, and thereaction solution was extracted with ethyl acetate (20 mL*3), and theorganic phase was washed with 10 mL saturated brine, dried overanhydrous sodium sulfate, concentrated, and separated by silica gelcolumn to afford 0.8 g of light yellow solid. Yield: 60%. LC-MS (APCI):m/z=311(M+1)⁺.

Step 7: Synthesis of Compound3-ethynyl-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-amine

N-(1-methyl-1H-pyrazol-4-yl)-3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-8-amine(0.8 g, 2.58 mmol) was dissolved in 10 mL of tetrahydrofuran,tetrabutylammonium fluoride (1.35 g, 5.16 mmol) was added, the reactionwas stirred at room temperature for 1 hour. The solvent was removed byrotary evaporation, 10 mL of water was added, and the reaction solutionwas extracted with ethyl acetate (10 mL*3), and the organic phase waswashed with 10 mL saturated brine, dried over anhydrous sodium sulfate,concentrated, and separated by silica gel column to afford 0.52 g oflight yellow solid. Yield: 85%. LC-MS(APCI): m/z=239(M+1)⁺.

Step 8: Synthesis of CompoundN-(4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)-3-(trifluoromethyl)benzamide

N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide (125 mg, 0.31mmol),3-ethynyl-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-amine(90 mg, 0.38 mmol), Pd(PPh₃)₄ (11 mg, 0.01 mmol), CuI (4 mg, 0.02 mmol)and 0.12 mL N,N-diisopropylethylamine were added to 5 mL of DMF, theatmosphere was replaced with nitrogen for 3 times, the reaction washeated to 90° C., and reacted for 3 hours. After the completion ofreaction, the reaction was cooled to room temperature, 20 mL of waterwas added, and the reaction solution was extracted with ethyl acetate(10 mL*3), and the organic phase was washed with 10 mL saturated brine,dried over anhydrous sodium sulfate, concentrated, and separated bysilica gel column to afford 90 mg of light yellow solid. Yield: 56%.LC-MS(APCI): m/z=516(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (s, 1H),9.43 (s, 1H), 8.32 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.23 (d, J=5.7 Hz,1H), 8.04 (d, J=2.3 Hz, 1H), 8.01 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.93(s, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.73 (dd, J=8.4, 2.3 Hz, 1H), 7.58 (d,J=0.9 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.42 (d, J=5.6 Hz, 1H), 3.86 (s,3H). 2.52 (s, 3H).

Example 12 Preparation ofN-(4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)-2-(trifluoromethyl)isonicotinamide(Compound I-12)

The title compound I-12 was prepared according to the synthetic methoddescribed in Example 11, and compoundN-(3-iodo-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide was used toreplace N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide in step8. LC-MS(APCI): m/z=517(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s,1H), 9.42 (s, 1H), 9.00 (d, J=5.0 Hz, 1H), 8.38 (s, 1H), 8.22 (dd,J=10.2, 5.3 Hz, 2H), 8.02 (d, J=11.6 Hz, 2H), 7.92 (s, 1H), 7.71 (dd,J=8.3, 2.3 Hz, 1H), 7.58 (s, 1H), 7.38 (d, J=8.4 Hz, 1H), 6.42 (d, J=5.6Hz, 1H), 3.86 (s, 3H), 2.54 (s, 3H).

Example 13 Preparation of4-methyl-N-(4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)-3-(trifluoromethyl)benzamide(Compound I-13)

The title compound I-13 was prepared according to the synthetic methoddescribed in Example 11, and compoundN-(3-iodo-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide was usedto replace N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide instep 8. LC-MS(APCI): m/z=530(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ10.45 (s,1H), 9.42 (s, 1H), 8.26 (d, J=1.7 Hz, 1H), 8.23 (d, J=5.7 Hz, 1H), 8.17(d, J=7.5 Hz, 1H), 8.03 (d, J=2.3 Hz, 1H), 8.01 (s, 1H), 7.92 (s, 1H),7.72 (dd, J=8.3, 2.3 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.58 (d, J=0.8 Hz,1H), 7.35 (d, J=8.5 Hz, 1H), 6.42 (d, J=5.7 Hz, 1H), 3.86 (s, 3H), 2.53(d, J=2.0 Hz, 3H), 2.49 (s, 3H).

Example 14 Preparation of4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(3-(trifluoromethyl)phenyl)benzamide(Compound I-14)

The title compound I-14 was prepared according to the synthetic methoddescribed in Example 11, and compound3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide was used toreplace N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide in step8. LC-MS(APCI): m/z=516(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (s,1H), 9.44 (s, 1H), 8.26 (s, 1H), 8.24 (d, J=5.6 Hz, 1H), 8.21 (d, J=2.0Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 8.03 (s, 1H), 7.97-7.91 (m, 2H),7.64-7.57 (m, 2H), 7.54 (d, J=8.1 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 3.86(s, 3H), 2.60 (s, 3H).

Example 15 Preparation of4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide(Compound I-15)

The title compound I-15 was prepared according to the synthetic methoddescribed in Example 11, and compound3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamidewas used to replaceN-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide in step 8.LC-MS(APCI): m/z=628(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.62 (s, 1H),9.43 (s, 1H), 8.24 (d, J=5.4 Hz, 2H), 8.20 (s, 1H), 8.10 (d, J=8.9 Hz,1H), 8.03 (s, 1H), 7.97-7.91 (m, 2H), 7.71 (d, J=8.5 Hz, 1H), 7.58 (s,1H), 7.54 (d, J=8.1 Hz, 1H), 6.43 (d, J=5.7 Hz, 1H), 3.86 (s, 3H), 3.62(s, 2H), 2.80 (s, 4H), 2.60 (s, 3H), 2.55 (s, 4H), 2.48 (s, 3H).

Example 16 Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)urea(Compound I-16)

The title compound I-16 was prepared according to the synthetic methoddescribed in Example 11, and compoundI-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-iodo-4-methylphenyl)urea wasused to replace N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamidein step 8. LC-MS(APCI): m/z=566(M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.42(s, 1H), 9.20 (s, 1H), 8.91 (s, 1H), 8.23 (d, J=5.6 Hz, 1H), 8.13 (d,J=2.4 Hz, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.79 (d, J=2.2 Hz, 1H),7.64-7.57 (m, 3H), 7.32 (dd, J=8.3, 2.3 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H),6.42 (d, J=5.6 Hz, 1H), 3.86 (s, 3H), 2.45 (s, 3H).

Biological Activity Assay

Biological Example 1: Biochemical Kinase Analysis

Reagents and materials: ABL (ThermoFisher, Cat. No. PV3585),ABL^(T315I)(Thermo Fisher, Cat. No. PR7429B), Ret (Carna, Cat. No.08-159-10 ug), RET^(V804M), Active (Signalchem, Cat. No. R02-12GG), ATP(Sigma, Cat. No. A7699-1G), DMSO (Sigma, Cat. No. D2650), 96-well plate(Corning, Cat. No. 3365), 384-well plate (Greiner, Cat. No. 784076),buffer solution (Thermo Fisher, Cat. No. PR4876B).

Specific Assay Method:

Compound formulation: The test compounds were dissolved in DMSO toprepare a 20 mM stock solution. Before use, the compounds were dilutedin DMSO to 0.1 mM, and diluted into 11 concentrations with a 3-foldgradient. When addition, dilutions of 4-fold final concentration werethen made with buffer solution.

Kinase assay method: After preparing the buffer, the enzyme was mixedwith pre-formulated and diluted compounds of different concentrations induplicate for each concentration, and placed at room temperature for 30minutes. The corresponding substrate and ATP were added thereto, andreacted at room temperature for 60 minutes (both a negative and apositive control were set). After the reaction, antibody was added fordetection, Evnvision detection was carried out after 60 minutesincubation at room temperature, and data was collected. Data analysisand fitting were made according to XLfit5 software.

Compounds of the present disclosure were tested in the above kinaseinhibition assay, and it is found that the compounds of the presentdisclosure have potent activity against ABL, ABL^(T315I), Ret andRET^(V804M). Results of representative example compounds were summarizedin Table 1 below:

TABLE 1 Example ABL ABL^(T315I) Ret RET^(V804M) No. IC₅₀ (nM) IC₅₀(nM)IC₅₀ (nM) IC₅₀(nM) Example 1 3.91 9.05 0.88 12.22 Example 2 6.65 10.130.32 2.69 Example 3 1.89 27.46 0.25 23.12 Example 4 4.93 7.69 — —Example 5 3.33 3.44 — — Example 6 1.60 65.05 — — Example 7 32.12 — — —Example 8 2.55 6.47 — — Example 9 0.93 19.93 — — Example 10 2.70 — — —Example 11 4.18 57.20 — — Example 12 2.24 — — — Example 13 9.88 67.18 —— Example 14 4.91 12.62 0.49 9.92 Example 15 3.24 4.28 0.37 1.42 Example16 82.91 — — —

Biological Example 2: Cell Proliferation Analysis

The inhibitory effect of the example compounds on Ba/F3 parental, Ba/F3Bcr-Abl^(T315I), K562, Ba/F3 KIF5B-RET, BaF3 FLT3-ITD cell activity wasdetermined.

Materials and reagents: RPMI-1640 medium (GIBCO, Catalog No. A10491-01),fetal bovine serum (GIBCO, Catalog No. 10099141), antibiotics(Penicillin-Streptomycin), IL-3(PeproTech), promycin; cell lines: Ba/F3parental, Ba/F3 Bcr-Abl^(T315I), Ba/F3 KIF5B-RET, BaF3 FLT3-ITD,(purchased from American type culture collection, ATCC), K562 live celldetection kit CellTiter-Glo4(Promega, Catalog No. G7572), 96-well blackwall transparent flat bottom cell culture plate (Corning, Catalog No.3340).

Test method: 1. Preparation of cell plate: Ba/F3 parental, Ba/F3Bcr-Abl^(T315I K)563, Ba/F3 KIFSB-RET, BaF3 FLT3-ITD cells wererespectively seeded in 96-well plates, and 8 ng/ml IL-3 was added to theBa/F3 cells, and the cell plates were placed in a carbon dioxideincubator and cultured overnight. 2. The test compounds were dissolvedin DMSO, 9 compound concentrations were made with a 3.16-fold gradientdilution in triplicate. 3. Treatment of the cells with compounds: Thecompounds were transferred to the cell plate with a startingconcentration of 10 μM. The cell plate was placed in a carbon dioxideincubator for 3 days. 4. Detection: CellTiter-Glo agent was added to thecell plate, and incubated at room temperature for 30 minutes tostabilize the luminous signal. PerkinElmer Envision multi-label analyzerwas used for reading, wherein A represents IC₅₀≤50 nM, B represents IC₅₀is 50-100 nM, C represents IC₅₀ is 100-500 nM, D represents IC₅₀ is500-1000 nM, D represents IC₅₀>1000 nM.

Compounds of the present disclosure were tested in the above Cellproliferation inhibition assay, and it is found that the compounds ofthe present disclosure have potent activity on tumor cell K562 and Ba/F3Bcr-Abl^(T315I) as well as outstanding selectivity over tumor cell Ba/F3parental. Results of the inhibitory effect of representative examples onthe in vitro proliferation of cancer cells were summarized in Table 2below.

TABLE 2 IC₅₀ (nM) Example Ba/F3 Ba/F3 Ba/F3 Ba/F3 BaF3 No. parental K562BCR-ABL BCR-ABL^(T315) KIF5B-RET FLT3-ITD Example 1 837.78 0.28 5.6315.04 10.09 17.66 Example 2 945.32 0.50 5.10 16.98 6.02 10.00 Example 31342.03 0.16 4.75 101.42 26.45 67.71 Example 4 313.50 3.80 19.66 50.20 —— Example 5 339.89 1.32 10.57 87.98 — — Example 6 5232.49 6.56 9.61 — —— Example 7 619.57 4.53 — 291.31 — — Example 8 926.52 0.96 6.29 35.80 —— Example 9 4280.69 0.32 2.75 — — — Example 10 2677.24 1.27 17.27 56.10— — Example 11 770.33 0.26 4.76 143.84 — — Example 12 1888.76 0.27 7.75— — — Example 13 1223.31 1.30 15.59 162.35 — — Example 14 1551.91 0.979.02 24.85 15.82 23.00 Example 15 279.61 0.76 12.84 25.16 4.56 1.14Example 16 1366.86 12.11 — — — —

The above is detailed description of the present disclosure inconjunction with specific embodiments, and it cannot be assumed that thespecific implementation of the present disclosure is limited to thesedescriptions. For ordinary person skilled in the technical field towhich the present disclosure pertains, without deviating from theconcept of the present disclosure, various simple deductions orsubstitutions may be made, which should be regarded as falling withinthe protection scope of the present disclosure.

What is claimed is:
 1. A compound of formula (I-1), or apharmaceutically acceptable salt thereof:

wherein, X₁, X₂, X₃ and Y are each independently selected from N and CH,and at least one of X₁, X₂, X₃ and Y is N; ring A is C₆₋₁₀ aryl or 5- to12-membered heteroaryl; R₁ and R₃ are each independently absent or areH, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, —NR₁₂R₁₃, C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl,wherein the said C₁₋₆ alkyl is optionally substituted with one, two orthree groups selected from C₁₋₃ alkyl, hydroxy and C₁₋₃ alkoxy; R₂ isabsent or is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl or 4- to7-membered heterocyclyl; wherein the said C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl and 4- to 7-membered heterocyclyl are each optionallysubstituted by one, two or three R₁₄; wherein R₁ and R₂, or R₂ and R₃can be combined to form a C₅₋₇ cycloalkyl ring or 5- to 7-memberedheterocyclyl ring, and wherein the said C₅₋₇ cycloalkyl ring and 5- to7-membered heterocyclyl ring are each independently substituted by one,two or three R₁₄; R₄ is H, halogen, hydroxy, amino, C₁₋₆ alkyl, C₁₋₆alkoxy, C₃₋₇ cycloalkyl or 4- to 7-membered heterocyclyl; L is selectedfrom —C(O)NR₉—, —NR₉C(O)— and

ring B is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl; R₁ is absent or isH, halogen, cyano, hydroxy, amino, C₁₋₆ alkyl or C₁₋₆ alkoxy; R₆ and R₇are each independently absent or are H, halogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —NR₁₂R₁₃, C₃₋₇cycloalkyl or 4- to 7-membered heterocyclyl, wherein the said C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-memberedheterocyclyl are optionally substituted by one, two or three R₁₄; R₈ isabsent or is H or 5- to 7-membered heteroaryl, wherein the said 5- to7-membered heteroaryl is optionally substituted by one, two or threeR₁₅; wherein R₅ and R₆, R₆ and R₇, or R₇ and R₈ can be combined to forma C₅₋₇ cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ arylring or 5- to 12-membered heteroaryl ring, and wherein the said C₅₋₇cycloalkyl ring, 5- to 7-membered heterocyclyl ring, C₆₋₁₀ aryl ring and5- to 12-membered heteroaryl ring are each independently substituted byone, two or three R₁₄; R₁₂ and R₁₃ are each independently H or C₁₋₆alkyl; or R₁₂ and R₁₃ together with the nitrogen to which they areattached form a 4- to 7-membered heterocyclyl ring, wherein the formed4- to 7-membered heterocyclyl ring is optionally substituted by one, twoor three R₁₅; each R₁₄ is independently selected from halogen, cyano,hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, —NR₁₆R₁₇, —C(O)NR₁₈R₁₉, C₃₋₇cycloalkyl and 3- to 7-membered heterocyclyl, wherein the said C₃₋₇cycloalkyl and 3- to 7-membered heterocyclyl are optionally substitutedby one, two or three R₁₅; each R₁₅ is independently selected fromhalogen, hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy and —NR₂₀R₂₁; and R₉, R₁₆,R₁₇, R₁₈, R₁₉, R₂₀ and R₂₁ are each independently H or C₁₋₃ alkyl. 2.The compound of claim 1, which is a compound of formula (II-1) or apharmaceutically acceptable salt thereof:

wherein, W and V are each independently selected from CR₁ and N;provided that one of W and V is N, and W and V are not N at the sametime; and Y, X₁, X₂, X₃, R₁, R₂, R₃, R₄, L, ring B, R₅, R₆, R₇ and R₈are as defined in claim
 1. 3. The compound of claim 1, which is acompound of formula (III-1) or a pharmaceutically acceptable saltthereof:

wherein, Y, X₁, X₂, X₃, R₁, R₂, R₃, R₄, L, ring B, R₅, R₆, R₇ and R₈ areas defined in claim
 1. 4. The compound of claim 1, wherein, ring B isselected from benzene, pyridine, isoxazole, quinoline and benzothiazole.5. The compound of claim 3, which is a compound of formula (IIIa-1) or apharmaceutically acceptable salt thereof:

wherein, X₁ and X₃ are each independently selected from N and CH, and atleast one of X₁ and X₃ is N; R₂ is selected from C₁₋₆ alkyl, C₃₋₇cycloalkyl and 4- to 7-membered heterocyclyl; wherein the said C₁₋₆alkyl, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl are eachoptionally substituted by one or two R₁₄; R₄ is selected from H, halogenand C₁₋₆ alkyl; L is selected from —C(O)NH—, —NHC(O)— and

R₆ is selected from H, halogen, C₁₋₆ alkyl and C₁₋₆ haloalkyl; U₁ isselected from CH and N; U₂ is selected from CR₈ and N; U₃ is selectedfrom CR₇ and N; R₇ is selected from H, halogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-memberedheterocyclyl, wherein the said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl are optionallysubstituted by one, two or three R₁₄; R₈ is selected from H and 5- to7-membered heteroaryl, wherein the said 5- to 7-membered heteroaryl isoptionally substituted by one, two or three R₁₅; each R₁₄ isindependently selected from halogen, cyano, hydroxy, C₁₋₆ alkyl, C₁₋₆alkoxy, C₃₋₇ cycloalkyl and 3- to 7-membered heterocyclyl, wherein thesaid C₃₋₇ cycloalkyl and 3- to 7-membered heterocyclyl are optionallysubstituted by one, two or three R₁₅; and each R₁₅ is independentlyselected from halogen, hydroxy, C₁₋₃ alkyl and C₁₋₃ alkoxy.
 6. Thecompound of claim 5, which is a compound of formula (IIIa-2) or apharmaceutically acceptable salt thereof:

wherein, X₁ and X₃ are each independently selected from N and CH, and atleast one of X₁ and X₃ is N; R₂ is selected from C₁₋₆ alkyl, C₃₋₇cycloalkyl and or 4- to 7-membered heterocyclyl; wherein the said C₁₋₆alkyl, C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl are eachoptionally substituted by one or two R₁₄; R₄ is selected from H, halogenand C₁₋₆ alkyl; L is selected from —C(O)NH—, —NHC(O)— and

R₇ is selected from H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl, wherein the said C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-memberedheterocyclyl are optionally substituted by one, two or three R₁₄; R₈ isselected from H and 5- to 7-membered heteroaryl, wherein the said 5- to7-membered heteroaryl is optionally substituted by one, two or threeR₁₅; each R₁₄ is independently selected from halogen, cyano, hydroxy,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 3- to 7-memberedheterocyclyl, wherein the said C₃₋₇ cycloalkyl and 3- to 7-memberedheterocyclyl are optionally substituted by one, two or three R₁₅; andeach R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl andC₁₋₃ alkoxy.
 7. The compound of claim 6, which is a compound of formula(IIIa-3) or a pharmaceutically acceptable salt thereof:

wherein, X₁ and X₃ are each independently selected from N and CH, and atleast one of X₁ and X₃ is N; L is selected from —C(O)NH—, —NHC(O)— and

R₇ is selected from H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl and 4- to 7-membered heterocyclyl, wherein the said C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 4- to 7-memberedheterocyclyl are optionally substituted by one, two or three R₁₄; R₈ isselected from H and 5- to 7-membered heteroaryl, wherein the said 5- to7-membered heteroaryl is optionally substituted by one, two or threeR₁₅; each R₁₄ is independently selected from halogen, cyano, hydroxy,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl and 3- to 7-memberedheterocyclyl, wherein the said C₃₋₇ cycloalkyl and 3- to 7-memberedheterocyclyl are optionally substituted by one, two or three R₁₅; andeach R₁₅ is independently selected from halogen, hydroxy, C₁₋₃ alkyl andC₁₋₃ alkoxy.
 8. The compound of claim 1, wherein R₇ is selected from Hand C₁₋₃ alkyl optionally substituted by one or two R₁₄.
 9. The compoundof claim 8, wherein R₇ is selected from the following groups:


10. The compound of claim 1, wherein R₈ is selected from H andimidazolyl substituted with a C₁₋₃ alkyl.
 11. A compound, which isselected from the following:

or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition, comprising a compound or a pharmaceutically acceptable saltthereof according to claim 1, and pharmaceutically acceptableexcipient(s).